A female newborn, second child of healthy and nonconsanguineous parents, was delivered at 41+4 weeks of gestation by caesarean section. Pregnancy was naturally conceived and uneventful, as well as family history. Apgar scores were 9 and 9, at 1 and 5 minutes respectively. At birth, anthropometric measurements were as follows: weight 3440 g (43rd centile), length 49 cm (15th centile) and occipitofrontal circumference (OFC) 33.5 cm (17th centile). The patient was referred from a first level birthing center to our neonatal intensive care unit (NICU) soon after birth. At admission, physical examination showed frontal bossing, medially sparse eyebrows, hypertelorism, microphthalmia, epicanthal folds, down slanted palpebral fissures, depressed nasal bridge, bulbous tip, anteverted nares, long philtrum, and small mouth. Abundant retronuchal skin, posteriorly rotated and dysplastic ears with thick helix, tragus hypoplasia and pre-auricular pit, in addition to micrognathia completed the craniofacial profile (Figure 1a). Single umbilical artery, anorectal malformation (vestibular fistula, Figure 1b) with the anal outlet within the vaginal fornix, which however allowed regular emission of meconium, and increased plantar folds (Figure 1c) were also observed. Axial hypotonia and decreased archaic reflexes marked her neurological features.
Our patient was initially supported by total parenteral nutrition, performed for the first 48 hours, due to poor suction not coordinated with deglutition. The calibration of the perineal fistula, started soon after birth and then performed every two weeks, allowed spontaneous emission of faeces. Opthalmological examination detected chorioretinal and iris colobomas of the left eye. Neonatal screening revealed congenital hypothyroidism, then confirmed on day 9 of life (TSH 19.4 mIU/L, normal values [n.v.] 0.73-8.35; fT4 0.70 ng/dL, n.v. 0.93-1.99), treated with replacement therapy with levothyroxine. Thyroid ultrasound (US) documented no abnormalities. Head and abdominal US showed normal findings (regular view of gallbladder during fasting, no dilation of the intra- and extrahepatic biliary tracts), and hip echography disclosed physiological immaturity, corresponding to Graf stage IB. Conversely, heart US detected large foramen ovale along with "bovine" aortic arch, and ostium secundum type atrial septal defect (ASD). The diagnostic suspicion of CES was raised based on the association of chorioretinal and iris colobomas, auricular anomalies and anorectal malformation. Standard and molecular cytogenetic analyses were then performed. Karyotype revealed a female set with 47 chromosomes due to a small supernumerary acrocentric marker, and comparative genomic hybridization (CGH) array (9.5 Kb resolution, genome assembly GRCh37.p13) identified a partial tetrasomy of about 3 Mb of the long arm of chromosome 22, arr22q11.1q11.21(16054691_19010508)x4. Cytogenetic molecular analysis was extended to parents, who showed normal findings, thus outlining the sporadic occurrence of the chromosomal abnormality.
Persistent hypoglycemia (lower glycemic value 20 mg/dl) occurred since the first days, and was treated with high rate infusion (up to 15 mg/kg/min) of intravenous glucose until day 45. Results of extensive endocrine tests, and biochemical investigations performed during hypoglycemia are shown in Table 1. The baby had severe cortisol deficiency with normal plasmatic values of adrenocorticotropic hormone (ACTH). Plasmatic levels of growth hormone, basal insulin, C-peptide were low as well, while prolactin ones were within lower normal range (Table 1).
Table 1. Endocrine and biochemical investigations during hypoglycemia. GH: Growth hormone; ACTH: Adrenocorticotropic hormone; FSH: follicle-stimulating hormone; LH: Luteinizing hormone; TSH: Thyroid stimulating hormone; fT3: free Thyroxine 3; fT4: free Thyroxine 4.
Insulin
(2.6-24.9 mU/L)
|
C-peptide
(1.1-4.4 mg/L)
|
Cortisol
(6.2-19.4 mg/dl)
|
GH
(0-6 mg/L)
|
ACTH
(5-55 ng/L)
|
Prolactin
(4.79-23.3 mg/L)
|
FSH
UI/L
|
LH
UI/L
|
TSH
(1.2-17 mIU/L)
|
fT3
(2-4.4 ng/L)
|
fT4
(0.78-3.72 ng/L)
|
<0.4
|
0.09
|
0.11
|
<0.003
|
19.4
|
5.07
|
0.103
|
<0.1
|
19.4
|
2.22
|
0.70
|
Then, after glucagon stimulation test was performed, showing inadequate glycemic response and ruling out thus hyperinsulinism, intravenous (starting dose 2.5 mg/kg three times in a day) hydrocortisone therapy (later orally administered) was initiated on day 36, followed by gradual improvement of glucose homeostasis. In the meantime, on day 13, jaundice was also observed, associated to acholic stools and hyperchromic urine, subtending an increase of conjugate bilirubin, markers of cytolysis and cholangiolysis, and bile acids (Table 2). Therefore, ursodeoxycholic acid and liposoluble vitamins treatment was also started.
Table 2. Hepatic profile of our patient before treatment. ALT= Alanine amonitransferase; AST= aspartate aminotransferase; GGT= Gamma-glutamyl transferase; TSB/D=Total serum bilirubin/direct bilirubin.
Serum bile acids
(0.0-8.0 umol/L)
|
GGT
(5-36 U/L)
|
AST
(0-84 U/L)
|
ALT
(0-60 U/L)
|
TSB/D
(<12/<0.30 mg/dl)
|
135.5
|
1117
|
248
|
355
|
5.81/5.09
|
The following clinical evolution was regular, without further episodes of hypoglycemia and progressive regression of cholestasis. In the suspicion of congenital hypopituitarism, a brain MRI was subsequently performed. It demonstrated hypoplasia of the pituitary gland, agenesis of the stalk and ectopic neurohypophysis (EPP), in addition to hypoplastic corpus callosum. The subsequent clinical course was characterized, at about one month of age, by a late-onset sepsis sustained by methicillin-resistant staphylococcus epidermidis, treated with intravenous teicoplanin. Hearing screening through transient-evoked otoacoustic emissions (TEOAEs) revealed abnormal results. In order to ascertain and characterize the hearing loss, an audiological assessment was started. It included serial auditory brainstem response (ABR) evaluations at 2 and 4 months of age, which detected monolateral left response threshold at 60 dB (decibel) HL (hearing level) according to moderate hypoacusis, which however did not require to date any treatment.
She was discharged at age 2 months, and included in a multidisciplinary follow-up (endocrinological, neurodevelopmental, surgical, cardiological, ophthalmological, audiological, orthopedic). A home glycemic monitoring was started, which documented adequate blood glucose profile control with hydrocortisone at an oral dose of 2.5 mg/kg/die, divided in three times a day, while levothyroxine treatment was effective to normalize plasmatic TSH and fT4 values.
She currently is 7 months old and shows, according to World Health Organization growth chart for neonatal and infant close monitoring [4], a severe global growth failure: weight 5110 g (<0.4th centile, -3.38 standard deviations, SD), length 54 cm (<0.4th centile, -5.75 SD), OFC 38 cm (<0.4th centile, -3.67 SD). Neurological assessment detected a developmental delay, with central type axial hypotonia and normal osteotendinous reflexes. She can sit unsupported, turn the head, follow and reach an object (red cube and suspended red ring) in the midline with both her hands. Hip US identified ripening delay of the right joint (2B Graf stage), for which X-Ray investigation is presently planned. In addition, heart US shows patent foramen ovale with not relevant left-to-right shunt. During steroid replacement therapy, hormone investigations indicated low ACTH (<1.5 ng/L, n.v. 7.2-63.2 ng/L) and normal cortisol levels. She started GH replacement treatment, and is continuing oral hydrocortisone at the dose of 0.85 mg/kg/die, along with ursodeoxycholic acid and levothyroxine. Such therapy allows adequate control of glycemic and thyroid profiles, as well as of cholestasis (TSB 0.29 mg/dl, DSB 0.2 mg/dl), although gamma-glutamyl transferase (GGT) and transaminases still show increased levels (GGT 1945 U/L, n.v. 5.0-32.0 U/L; AST 253 U/L, n.v. 15.0-55.0 U/L; ALT 282 U/L, n.v. 5.0-33.0 U/L). The other routine blood tests and US (head and abdomen) evaluations show no further abnormalities. She still undergoes periodic calibrations of the vestibular fistula, waiting for the already planned corrective intervention.