Phenotype-to-genotype description of prenatal suspected and postnatal discovered upper limb anomalies: a retrospective cohort study.

doi:10.21203/rs.3.rs-4693217/v1

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Phenotype-to-genotype description of prenatal suspected and postnatal discovered upper limb anomalies: a retrospective cohort study.

https://doi.org/10.21203/rs.3.rs-4693217/v1

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This is a retrospective cohort study to evaluate phenotype and genotype characteristics of a prenatal and postnatal cohort with upper limb anomalies from January 2007 to December 2021 in one tertiary referral center for Fetal Medicine. All prenatally on ultrasound suspected upper limb anomalies, such as transverse and longitudinal reduction defects, polydactyly, and syndactyly were evaluated. Additionally, children referred to the Congenital Hand team in the same center with upper limb anomalies that were not identified prenatally, were also evaluated separately.

The prenatal group included 199 pregnancies: 64 transverse and 19 longitudinal reduction defects, 103 polydactylies, and 13 cases with syndactyly. The majority of cases with longitudinal reduction defects (n=10, 52.6%), polydactyly (n=62, 60.2%), and syndactyly (n=10, 76.9%) were non-isolated, as opposed to transverse reduction defects which were generally isolated (n=41, 64.1%). The Congenital Hand Team received 362 new referrals of children with upper limb anomalies that were not identified prenatally. These cases included 49 transverse and 22 longitudinal reduction defects, 226 polydactylies, and 65 syndactlylies. A chromosomal or monogenic abnormality was identified in 76/199 (38.2%) cases of the prenatal group and in 31/362 (8.6%) cases of the postnatal group.

Prenatal identification of minor defects of the digits holds a challenge, since we observed more postnatal than prenatal cases. The majority of cases with isolated anomalies in both groups had no underlying chromosomal, monogenic or syndromic cause, as compared to the non-isolated cases. Conducting structural anomaly scans and genetic counselling are crucial to assess the risk of genetic abnormalities.

Health sciences/Health care/Medical imaging/Ultrasonography

Health sciences/Health care/Medical imaging/Bone imaging

prenatal ultrasound

upper limb anomalies

reduction defect

polydactyly

syndactyly

Congenital anomalies affect approximately 2.5% of all newborns¹. Limb anomalies of the upper and lower limbs are frequently observed, with an estimated prevalence of 39 per 10.000 pregnancies in the Netherlands¹. Polydactyly is the most frequently observed upper limb anomaly followed by reduction defects, and syndactyly¹. Polydactyly is the occurrence of complete or partial extra digit(s), with or without a bony content. Polydactyly is classified as radial if the extra digit is on the thumb side and as ulnar when the extra digit is on the side of the little digit². A reduction defect is the absence, aplasia or hypoplasia of skeletal structures of the limb: transverse when the distal part of the limb is absent, and longitudinal when the long axis of a limb is affected^2,3. A syndactyly is the (partial) fusion of two or more digits².

Considering the significant role that upper limbs play in a child's psychosocial and motor development, it is crucial to provide information, support, and guidance by a multidisciplinary team to parents and their child when an upper limb anomaly is identified in the prenatal or postnatal period. Although the majority of children appear to adjust well to their condition, this is by no means the case for all children⁴. Although surgeons and parents may be good judges of functional outcomes, quality of life can only really be accurately measured if self-reported⁴. Reconstructive operations could have a positive impact on the function of the limbs, a child’s self-confidence and self-image⁴. Prenatal or postnatal genetic testing can be offered to define the underlying genetic etiology and the recurrence risk in a future pregnancy. Additionally, a prenatal diagnosis empowers parents with informed reproductive choices and enables planning of optimal neonatal and surgical care⁵.

The aim of this study was to evaluate the phenotype and genotype characteristics of a prenatal group of fetuses with suspected upper limb anomalies, including transverse and longitudinal reduction defects, polydactyly, and syndactyly. Additionally, a postnatal group of children with the same upper limb anomalies, not identified prenatally, was also described. The comparison in the phenotype-to-genotype characterization between the prenatal and postnatal group will support healthcare providers in advising and informing parents during parental genetic counselling.

Dutch prenatal healthcare system

In the Netherlands, prenatal screening occurs majorly in primary and secondary healthcare centers as part of a government led national screening program^6–8. All pregnant women are offered a first trimester viability and dating scan around 10 weeks of pregnancy. Additionally, women can opt for two structural anomaly scans, that is a second trimester anomaly scan since 2007 and in research setting a first trimester anomaly scan since 2021^6,7. Both structural anomaly scans have a strict protocol and are performed by trained sonographers. The second trimester protocol includes the visualization of the following structures of the upper arm, solely by 2D ultrasound: upper arm (including humerus), lower arm (including ulna and radius), posture of the wrist, and hand. Evaluation of the fingers is not mandatory. Moreover, all women are offered prenatal screening for fetal aneuploidy by the first trimester combined test (until 2021) or cell free fetal DNA testing (since 2017). Ultrasound examination in the third trimester is only performed for obstetric indications such as suspected growth restriction or abnormal presentation of the fetus. In contrast to low risk women, those with a high risk for fetal anomalies due to an obstetric history or underlying medical conditions, can opt for medical ultrasounds in the first and second trimester in a Fetal Medicine Unit. Genetic testing is not routinely offered, but only in case of a known familiar pathogenic variant or in case of suspected fetal anomalies in the current pregnancy.

If a fetal anomaly is suspected, all pregnant women are referred for an advanced ultrasound to a Fetal Medicine Unit⁸. In the North-West region of the Netherlands, this is conducted at Amsterdam University Medical Center (AUMC). Here the length of the fetal limb bones are assessed by using the charts of Chitty et al., 2002 [Chitty et al., 2002]. If an upper limb anomaly is suspected, parents or children are offered genetic testing. Moreover, referral to the Congenital Hand Team for additional counselling is also provided. This multidisciplinary team, consisting of clinical geneticists, plastic surgeons, rehabilitation doctors, and occupational therapists specialized in congenital anomalies of the upper limbs, offers prenatal and/or postnatal counselling and treatment until adulthood. Both the Fetal Medicine Unit and the Congenital Hand Team serve as referral centers for the same geographical area. Termination of pregnancy is permissible up to 24 weeks of gestation in the Netherlands.

Prenatal group

This is a retrospective cohort study of pregnant women who underwent prenatal ultrasound examinations at the Fetal Medicine Unit of AUMC from January 2007 and December 2021. We included all fetuses with the following fetal upper limb anomalies: transverse and longitudinal reduction defects, polydactyly, and syndactyly. After approval from the Medical Ethical Committee of AUMC (reference number W21_361 # 21.401), we subtracted prenatal data from the medical and obstetric history of the mothers, prenatal ultrasound findings, results of invasive genetic tests, and postnatal follow-up of the newborns. Additional information regarding postnatal findings was evaluated using the children’s electronic patient files. When data were missing, we contacted other healthcare providers (e.g. midwife or gynecologist) of the mothers for information on the outcome. We excluded pregnancies with other upper limb anomalies, such as dysplasia (e.g. contractures and lymphangioma).

In case of a termination of pregnancy, postnatal confirmation of the diagnosis occurred by macroscopic physical and/or pathological examination. If necessary, additional imaging including X-ray was performed. In cases without documentation of the postnatal examination, it was assumed that the postnatal findings were in accordance with prenatal findings.

Postnatal group

The postnatal group consisted of all live born children, who were seen by the Congenital hand team of AUMC between January 2007 and December 2021 with a transverse and longitudinal reduction defect, polydactyly, and syndactyly. All mothers had received their second trimester anomaly scan in the North-West region of the Netherlands. Duplicate cases were removed when the case was already included in the prenatal group.

Classification

Cases were grouped per affected axis (proximodistal, radioulnar or unspecified) according to the Oberg-Manske-Tonkin (OMT) classification for upper limb anomalies². The anomalies were classified as isolated (ISO) if no other fetal abnormality was observed during prenatal sonography (prenatal group) or during postnatal physical examination (postnatal group), and as non-isolated (NISO) when other structural anomalies were identified. In case of multiple anomalies of the upper limb, the case was classified as isolated and scored according to the most severe upper limb anomaly.

Outcomes of genetic testing were reported and classified as chromosomal or as monogenic. In cases with multiple anomalies without a genetic diagnosis, the case was classified as syndromic.

The performed genetic tests per case were dependent on the parents’ request and year of diagnosis. In the last decades, advancements in genetic evaluation have shifted from karyotyping to Whole Exome Sequencing (WES)^9–12. In case of suspected anomalies, rapid aneuploidy testing is the first tier test to examine aneuploidies, followed by chromosomal microarrays. Targeted molecular testing was mainly performed in families with known genetic pathogenic variants. Prenatal WES has been offered since 2019 in our unit, as opposed to a postnatal WES, which is available since 2012¹².

Descriptive analysis

For the descriptive analysis of both groups, the findings of prenatal and postnatal genetic testing were reported in numbers and percentages. Furthermore, we estimated the prevalence (per 10,000 pregnancies) and prenatal detection rates of the specific limb anomalies.

Prenatal group

Between 2007 and 2021, 485.000 women received a structural anomaly scan within the North-West region of the Netherlands (source unpublished data from the yearly ultrasound unit audit files of the Fetal Medicine Unit of AUMC, including the region’s primary care facilities). A total of 225 women was referred for ultrasound examinations due to suspected upper limb anomalies of which 26 (11.5%) could not be confirmed. A transverse reduction defect was finally identified in 66 cases, longitudinal reduction defect in 19, polydactyly in 124, and syndactyly in 16, of which the majority was non-isolated (Fig. 1). There was one lost to follow-up in the polydactyly group. All cases with genetic abnormalities are summarized in Tables 1 and 2, including the phenotypes. A genetic abnormality was identified in 76 of the 199 (38.2%) cases. The most commonly observed monogenic syndromes were Cornelia de Lange for reduction defects, Greig cephalopolysyndactyly and Bardet-Biedl for polydactyly, and Apert for syndactyly (Table 2).

Table 1

Genetic testing and results in n (%), divided in prenatal identified (only cases that were prenatally identified on sonography and confirmed after birth) and postnatal discovered (prenatally not identified during ultrasound examination, but discovered after birth). All the cases were categorized into three groups with abnormalities: chromosomal, monogenic, or syndromic. Chromosomal cases involve abnormalities in the chromosomes, monogenic cases are linked to single gene mutations, and syndromic cases exhibit multiple abnormalities without a known chromosomal or monogenic disorder causing them. It is expected that cases without any suspected chromosomal, monogenic, or syndromic causes are generally in good health.
Sonographic characteristics	PRENATALLLY IDENTIFIED n (%)					POSTNATALLY DISCOVERED n (%)
	Tested/total (n)	Genetic		Non-genetic		Tested/total (n)	Genetic		Non-genetic
	Tested/total (n)	Chromosomal	Monogenic	Syndromic	No additional diagnosis	Tested/total (n)	Chromosomal	Monogenic	Syndromic	No additional diagnosis
Reduction defect, transverse	64					49
Isolated, unilateral	14/40	-	-	-	40 (100%)	5/34	-	-	-	34 (100%)
Isolated, bilateral	1/1	-	-	-	1 (100%)	5/8	1 (12.5%)	3 (37.5%)	-	4 (50%)
Non-isolated	19/23	7 (30.4%)	4 (17.4%)	9 (39.1%)	3 (13.1%)	3/7	1 (14.3%)	-	5 (71.4%)	1 (14.3%)
Reduction defect, longitudinal	19					22
Isolated, unilateral	2/6	-	-	-	6 (100%)	2/11	-	-	-	11 (100%)
Isolated, bilateral	3/3	2 (66.7%)	1 (33.3%)	-	-	2/2	1 (50%)	-	-	1 (50%)
Non-isolated	9/10	3 (30%)	3 (30%)	2 (20%)	2 (20%)	6/9	-	1 (11.1%)	7 (77.8%)	1 (11.1%)
Polydactyly	103					226
Isolated, unilateral	2/12	-	-	-	12 (100%)	7/110	1 (0.9%)	1 (0.9%)	-	108 (98.2%)
Isolated, bilateral	6/29	-	1 (3.4%)	-	28 (76.6%)	10/94	-	2 (2.1%)	-	92 (97.9%)
Non-isolated	55/62	39 (62.9%)	7 (11.3)	11 (18.1%)	2 (3.2%)	16/22	2 (9.1%)	7 (31.8%)	6 (27.3%)	7 (31.8%)
Syndactyly	13					65
Isolated, unilateral	0/2	-	-	-	2 (100%)	2/32	-	1 (3.1%)	-	31 (96.9%)
Isolated, bilateral	0/1	-	-	-	1 (100%)	9/22	-	5 (22.7%)	-	17 (77.3%)
Non-isolated	10/10	1 (10%)	5 (50%)	4 (40%)	-	9/11	1 (9.1%)	4 (36.3%)	3 (27.3%)	3 (27.3%)
n = number

Table 2

Phenotype, genotype and postnatal findings of the prenatal group
Number	Prenatal phenotype	Genotype	Diagnosis (by which test)	Sonographic characteristics and additional postnatal findings
1–2	Reduction defect, isolated, bilateral	TAR syndrome (microdeletion 1q21.1)	TAR syndrome (micro array)	Radial ray defect.
3	Reduction defect, isolated, bilateral	Pathogenic variant in FGFR2 gene	FGFR2 related syndrome (WES)	Radial ray defect. Postnatal additional findings : bilateral renal agenesis and syndactyly
4–5	Reduction defect, non-isolated, unilateral	Trisomy 21	Down syndrome (QF PCR)
6–11	Reduction defect, non-isolated	Trisomy 18	Edwards syndrome (Karyotyping or QF PCR)
12	Reduction defect, non-isolated	PIK3CA gene mutation	PIK3CA related syndrome (gene panel)	Transversal reduction defect or the right hand, oligodactyly, lymphangioma from head to thorax
13	Reduction defect, non-isolated	FANCB gene mutation	Fanconi anemia type B (WES)	Fetal growth restriction, ventriculomegaly, small cerebellum, bilateral short humerus and ulna with radial ray defects. Left hand with rudimental thumb, contractures of both legs
14	Reduction defect, non-isolated	NIPBL gene mutation	Cornelia de Lange syndrome (targeted molecular testing)	Brachycephaly, hydrops, Dandy walker malformation, dextrocardia, hypoplastic left heart, bilateral radial ray defects, oligodactyly and rocker bottom feet
15	Reduction defect, non-isolated	Tetrasomy 9p	(micro array)	Mild ventriculomegaly, vermis hypoplasia, abnormal corpus callosum, retrognathia, AVSD, empty stomach, single umbilical artery, talipes equinovarus, and syndactyly
16	Reduction defect, non-isolated	DYNC2H1-gene mutations	Jeune syndrome (gene panel)	Bilateral short humerus and femur with an abnormal stature, short ribs and bilateral polydactyly
17	Reduction defect, non-isolated	NIPBL gene mutation	Cornelia de Lange syndrome (WES)	Micrognathia, clubfeet, reduction defect lower legs, polydactyly unilateral, radial ray defect unilateral, oligodactyly hand
18	Reduction defect, non-isolated	NIPBL gene mutation	Cornelia de Lange syndrome (targeted molecular testing)	Split hand, radius aplasia, rudimentary fingers,, hypoplastic nasal bone, ventricular septal defect
19	Reduction defect, non-isolated	NIPBL gene mutation,	Cornelia de Lange syndrome (targeted molecular testing)	Thick nuchal translucency, diaphragmatic hernia, micrognathia, absent nasal bone, absence of 3 fingers unilateral
20	Reduction defect, non-isolated	Triploidy (paternal)	Triploidy (QF PCR)	Holoprosencephaly, cardiomegaly, (A)VSD, oligodactyly unilateral, omphalocele, echogenic kidneys and bowels, growth restriction
21	Polydactyly, isolated, bilateral	Trisomy 13	Patau syndrome (QF PCR)
22	Polydactyly, isolated, bilateral	GLI3 gene mutation	Greig cephalopolysyndactyly syndrome (targeted molecular testing)	Polydactyly both hands. Sibling of number case 70.
23–52	Polydactyly, non-isolated	Trisomy 13	Patau syndrome (Karyotyping or QF PCR)
52–58	Polydactyly, non-isolated	Trisomy 18	Edwards syndrome (Karyotyping or QF PCR)
59	Polydactyly, non-isolated	1q21.1 duplication	1q21.1 duplication syndrome (micro array)	Diaphragmatic hernia, postaxial polydactyly both hands and feet, echogenic kidneys
60	Polydactyly, non-isolated	TMEM218 gene mutations	Meckel Gruber syndrome (WES)	Encephalocele, polydactyly, polycystic dysplastic kidneys
61	Polydactyly, non-isolated	GLI3 gene mutation	Greig cephalopolysyndactyly syndrome (WES)	Polydactyly (preaxial) hands and feet, mild ventriculomegaly.
62	Polydactyly, non-isolated	BBS4 gene mutations	Bardet-Biedl syndrome type 4 (WES)	Polydactyly bilateral hands and feet, echogenic kidneys
63	Polydactyly, non-isolated	MKKS gene mutations	Bardet-Biedl syndrome type 6 (WES)	Ulnar polydactyly hands and feet, echogenic kidneys
64	Polydactyly, non-isolated	TMEM218 gene mutations	Meckel Gruber syndrome (WES)	Encephalocele, bilateral polycystic kidneys, polydactyly bilateral hands and legs, single ventricle heart, talipes equinovarus
65	Polydactyly, non-isolated	EVC gene mutations	Ellis van Crefeld syndrome (WES)	Ulnar polydactyly, short bones
66	Polydactyly, non-isolated	DHCR7 gene mutations	Smith Lemli Opitz syndrome (targeted molecular testing)	Polydactyly, overlapping fingers,
67	Polydactyly, non-isolated	Trisomy 21	Down syndrome (QF PCR)	Hydrops and bilateral polydactyly (pre- or postaxial unknown), miscarriage at a gestational age of 11 weeks.
68	Polydactyly, non-isolated	BBS5 gene mutations	Bardet-Biedl syndrome type 5 (WES)	Polycystic kidneys, hypospadias, postaxial polydactyly, oligohydramnios
69	Polydactyly, non-isolated	Trisomy 13	Patau syndrome (NIPT only)
70	Polydactyly, non-isolated	GLI3 gene mutation	Greig cephalopolysyndactyly syndrome (targeted molecular testing)	Sibling of case 22. Prenatal suspicion of CCAM and polyhydramnios. CCAM was not confirmed after birth.
71	Syndactyly, non-isolated	Triploidy (maternal)	Triploidy (QF PCR)	Large head, small abdomen, horseshoe kidney, syndactyly unilateral, growth restriction
72	Syndactyly, non-isolated	FGFR2 gene mutation	Apert syndrome (targeted molecular testing)	Dolichocephaly, syndactyly bilateral, thick nuchal translucency
73	Syndactyly, non-isolated	TP63 gene mutation	Ectrodactyly - ectodermal dysplasia - cleft syndrome (targeted molecular testing)	Bilateral cleft lip, VSD, abnormal position of the toes and fingers, syndactyly dig 3–4 bilateral hands and also feet
74	Syndactyly, non-isolated	FGFR2 gene mutation	Apert syndrome (targeted molecular testing)	Abnormal profile (frontal bossing), large cerebellum, bilateral syndactyly
75	Syndactyly, non-isolated	Triploidy (maternal)	Triploidy (QF PCR)	Syndactyly hands, small thorax, AC and FL < p3, micrognathia, VSD, empty stomach
76	Syndactyly, non-isolated	GLI3 gene mutation	Greig cephalopolysyndactyly syndrome (targeted molecular testing)	Ventriculomegaly, poly- and syndactyly, VSD

Table 3

Phenotype, genotype and postnatal findings of the postnatal group
Number	Postnatal phenotype	Genotype	Diagnosis (by which test)	Characteristics on postnatal physical examination and other comments
1	Reduction defect, isolated, bilateral	Duplication 20q11.22	(micro array)	Hypoplastic thumb/brachydactyly
2	Reduction defect, isolated, bilateral	Duplication 10q24	Split-Hand-Split-Foot Malformation (micro array)	Cleft hand and foot syndrome
3–5	Reduction defect, isolated, bilateral	GDF5 gene mutation	Brachydactyly type C (WES)	Reduction defect dig 2–5
6	Reduction defect, non-isolated	Mosaic trisomy 18	(FISH/micro array)	Longitudinal defect of both lower arms with hypoplastic thumbs, proximal radio-ulnar synostosis, clinodactyly dig 5 bilateral, syndactyly toes
7	Reduction defect, non-isolated	TBX5 gene mutation	Holt-Oram syndrome (targeted molecular testing)	Radius hypoplasia, partial syndactyly dig 2 unilateral, VSD
8	Polydactyly, isolated, unilateral	Deletion 17p12-17p11.2	(micro array)	Postaxial polydactyly
9	Polydactyly, isolated, unilateral	FANCA gene mutations	Fanconi anemia (Mitomycine-C test)	Radial polydactyly, fanconi anemia
10	Polydactyly, isolated, bilateral	ERF gene mutation	Chitayat syndrome (WES)	Central polydactyly bilateral (dig 2)
11	Polydactyly, isolated, bilateral	GLI3 gene mutation	Greig cephalopolysyndactyly syndrome (unknown)	Polydactyly all limbs, syndactyly foot
12	Polydactyly, non-isolated	Deletion 1q21,1-q21.2	(micro array)	Bilateral preaxial polydactyly, microcephaly
13	Polydactyly, non-isolated	TBX3 gene mutation	Ulnar-mammary syndrome (WES)	Bilateral polydactyly, VSD, tracheomalacia, mamma aplasia
14	Polydactyly, non-isolated	TFAP2A gene mutation	Branchio-oculo-facial syndrome (targeted molecular testing)	Cleft palate, polydactyly
15	Polydactyly, non-isolated	HNRNPU gene mutation	Early infantile epileptic encephalopathy type 31 (unknown)	Scoliosis, syndactyly feet, preaxial polydactyly hands and feet, epilepsy, psychomotor retardation
16	Polydactyly, non-isolated	PUF60 gene mutation, BTD gene mutations	Verheij syndrome (WES)	Cleft lip, polydactyly unilateral hand, coloboma. BTD gene mutation is a VUS.
17	Polydactyly, non-isolated	CHD4 gene mutation	Sifrim-Hitz-Weiss syndrome (unknown)	Postaxial polydactyly hand (not typical for mutation, VUS), pes planovalgus deformity, cryptorchidism.
18	Polydactyly, non-isolated	Trisomy 21	Down Syndrome (QF PCR, karyotyping)	AVSD, radial polydactyly unilateral
19	Polydactyly, non-isolated	BBS10 gene mutations	Bardet-Biedl syndrome (WES)	Large kidneys, postaxial polydactyly unilateral
20	Polydactyly, non-isolated	BBS12 gene mutations	Bardet-Biedl syndrome (gene panel)	Polydactyly unilateral hand and both feet, dysplastic kidneys
21–23	Syndactyly, isolated, bilateral	GJA1 gene mutation	Oculo-dento-digital syndrome (targeted molecular testing)	Syndactyly dig 4 and 5 hands
24	Syndactyly, isolated, bilateral	BBS7 gene mutations	Bardet-Biedl syndrome (gene panel)	Syndactyly and polydactyly
25	Syndactyly, isolated, unilateral	RAF1 gene mutation	Noonan syndrome (targeted molecular testing)	Syndactyly hand dig 3–4, learning difficulties, clinodactyly
26	Syndactyly, isolated, unilateral	PIK3CA gene mutation	Megalencephaly-capillary malformation (gene panel)	Syndactyly dig 3–4, syndactyly feet, Cutis Marmorata Telangiectatica Congenita
27	Syndactyly, non-isolated, bilateral	FGFR2 gene mutation	Apert syndrome (targeted molecular testing)	Syndactyly and craniosynostosis
28	Syndactyly, non-isolated, bilateral	FGFR2 gene mutation	Apert syndrome (targeted molecular testing)	Frontal bossing, syndactyly both hands and feet, craniosynostosis
29	Syndactyly, non-isolated	BPTF gene mutation	Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies (WES)	VSD, bilateral syndactyly
30	Syndactyly, non-isolated	Distal deletion of 22q11	22q11 deletion syndrome (micro array)	Unilateral syndactyly dig3 and 4, ASD, retrognathia
31	Syndactyly, isolated, bilateral	GJA1 gene mutation	Oculo-dento-digital syndrome (targeted molecular testing)	Syndactyly dig 4 and 5 both hands

Postnatal group

The postnatal group consisted of 362 children. These cases included 49 transverse and 22 longitudinal reduction defects, 226 polydactylies, and 65 syndactlylies, of which the majority was non-isolated (Figure 2). A total of 42 out of 49 (86%) children presented with a transverse reduction defect of the digits, 5 (10%) in the lower arm (radius or ulna), and/or in 2 (4%) the whole hand was affected. In 14 out of 22 (64%) children with a longitudinal reduction defect, the anomaly occurred in the digit(s) only, in 5 (22%) in the lower arm (radius or ulna) and in 3 (14%) children the whole hand was affected. Reduction defects involving the humerus were not observed. All cases with genetic abnormalities are summarized in Tables 1 and 3, including the phenotypes. A genetic abnormality was identified in 31 of the 362 (8.2%) cases. The most observed monogenic syndromes were brachydactyly type C for reduction defects, Bardet-Biedl for polydactyly, and oculo-dento-digital syndrome and Apert for syndactyly (Table 3).

Prevalence

In total, there were 561 cases with anomalies, of which 199 were identified in the prenatal and 362 in the postnatal period. The estimated prenatal detection rates were 57% (64 of the 113) for transverse reduction defect, 46% (10 of the 41) for longitudinal reduction defect, 31% (103 of the 329) for polydactyly, and 17% (13 of the 78) for syndactyly. The estimated prevalence for the North-West region was 2.3 per 10,000 pregnancies for transverse reduction defects, 0.8 for longitudinal reduction defects, 6.7 for polydactyly and 1.6 for syndactyly, respectively.

This study demonstrated that the majority of cases with isolated anomalies in both the prenatal and postnatal group had no underlying chromosomal, monogenic or syndromic cause, while in the majority of the non-isolated cases an underlying genetic cause was found. An higher percentage of genetic abnormalities was seen in the prenatal group in comparison with the postnatal group. The substantial size of the postnatal group suggests a potential gap in prenatal of upper limb anomalies between 2007 and 2021.

The available literature on the prenatal detection of upper limb anomalies is primarily based on data gathered decades ago, while improvement in the prenatal anomaly identification has been observed on other fetal anomalies over the last few years^13–21. Reported prenatal detection rates of upper limb anomalies range between 22.8–42% (period 1990–2010)^13–21. Anomalies of the entire upper limb have higher sensitivities (70–100%), whereas anomalies affecting only the digits had the lowest sensitivities (4–19%)^20,21. This is in line with our finding that in 56 of the 71 (78.9%) children with postnatally discovered reduction defect, the anomaly occurred in the digit(s).

The high occurrence of chromosomal abnormalities in the non-isolated prenatal group of our study (26%) was similar to the findings of Paladini and colleagues (28%)²². In contrast, the postnatal group exhibited a lower percentage of chromosomal abnormalities (7/365, 1.9%). Additionally, the occurrence of monogenic abnormalities was higher in the prenatal group (21/199, 10.5%) than in the postnatal group (24/362, 6.6%). The expected structural anomalies are mainly in the urogenital, heart and nervous system^21,22.

The findings of this study are useful for healthcare providers who want to inform parents about the potential prenatal and postnatal outcomes. Notably, this study has one of the largest study populations with upper limb anomalies that has been described, with a total of 561 included cases.

The retrospective nature of this study is one of the study’s limitations. In the prenatal group, findings about postnatal examination were not always well documented after a termination of pregnancy and we assumed that all these cases were correctly identified when no additional specific classification was made postnatally. Moreover, since not all other fetuses have been systematically evaluated macroscopically after a termination of pregnancy, some upper limb anomalies may have been missed leading to an underestimation. In the postnatal group, we expect that all children with clinically relevant upper limb anomalies will be referred to the Congenital hand team. However, we expect that simple forms of polydactyly may also have been treated outside our tertiary hospital. Regional guidelines allow plastic surgeons in secondary hospitals to treat simple forms of polydactyly, which may also have contributed to an underestimation of the postnatal group. Therefore, we believe that the prenatal detection rate is polydactyly is an overestimation.

An early prenatal identification of abnormalities allows parents more time to consider whether they wish to have prenatal invasive testing. A genetic consultation should be offered as a standard workup to define the underlying genetic causes if a upper limb anomaly is suspected^21,22. Evaluation of the prenatal phenotype can help to determine if it is part of a genetic syndrome²³. For example, radial polydactylies are more observed in non-isolated cases compared to ulnar polydactylies²⁴. Furthermore, it is important to enquire about family history for upper limb anomalies, maternal medication use and intoxication to identify factors related to the anomaly^18,25.

If invasive diagnostics is requested by parents, rapid aneuploidy testing and microarray analysis are highly recommended as a first step, particularly in non-isolated cases^18,26. In the prenatal group, 53 of the 76 (70%) abnormalities were detectable by these tests (Table 2). Finally, Whole Exome Sequencing can be used to detect other genetic disorders. In case of isolated upper limb anomalies, particularly in unilateral anomalies, parents can be informed that chromosomal, monogenic and syndromic underlying causes are rare.

In conclusion, this study showed that the majority of cases with isolated limb anomalies in both the prenatal and postnatal group had no underlying chromosomal, monogenic or syndromic cause, while in the majority of the non-isolated cases an underlying genetic cause was found. For isolated unilateral anomalies, parents should be informed that most cases do not have an underlying genetic cause. Identification of minor defects of the hand and digits poses a challenge, given the larger size of the postnatal group compared to the prenatal group.

Data and code availability statement

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Acknowledgements

None

Author contribution

AA, MvD, IL, EvL and EP designed this study. JvD and FtC helped AA to write the manuscript after data extraction. MvD, IL, EvL, MvM and EP provided feedback on the report.

Funding

None

Ethical approval:

Approval from the Medical Ethical Committee of Amsterdam UMC (reference number W21_361 # 21.401).

Competing interests:

The authors declare no conflicts of interest.

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Phenotype-to-genotype description of prenatal suspected and postnatal discovered upper limb anomalies: a retrospective cohort study.

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Introduction

Methods

Dutch prenatal healthcare system

Prenatal group

Postnatal group

Classification

Descriptive analysis

Results

Prenatal group

Postnatal group

Prevalence

Discussion

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References

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