Zimmermanne Laband syndrome and infantile systemic hyalinosis: an enigma with two separate terms with overlapping features: case report and literature review

doi:10.21203/rs.3.rs-2321953/v1

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Case Report

Zimmermanne Laband syndrome and infantile systemic hyalinosis: an enigma with two separate terms with overlapping features: case report and literature review

https://doi.org/10.21203/rs.3.rs-2321953/v1

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published 13 Oct, 2023

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Background

Zimmermann-Laband Syndrome (ZLS) and infantile systemic hyalinosis (ISH) are extremely rare genetic disorders characterized by various spectrum manifestations. In spite of other case reports, this case has been reported by oral medicine specialists and oral and maxillofacial surgeons with overlapping features of both syndromes.

Case presentation

In this study, we reported a 2-year-old female patient with gingival growth and brought about embedded erupted teeth in both jaws. The new aspect of this case report attributed to multiple papulo-nodular skin lesions barely reported by a kind of literature. Surgical excision was performed under general anesthesia. At six months of follow-up after surgery, mastication, and breathing problems were significantly improved. Aesthetic in terms of gingival appearance was ameliorated.

Conclusions

Although both syndromes remain an enigma for specialists to date because of their ambiguous presentations, the timely diagnosis could be crucial for prognosis and prevention of further serious surcharge. Dentists could have an important role in the diagnosis of rare disorders.

Zimmermann-Laband Syndrome

infantile systemic hyalinosis

gingival enlargement

papulo-nodular lesions

case report

The classic form of infantile systemic hyalinosis (ISH) is an autosomal recessive disorder characterized by early onset skin lesions and other manifestations. Progressive deposition of amorphous hyaline material in different tissues of vital organs could lead to various presentations. In contrast to Zimmermann-Laband Syndrome (ZLS), ISH usually presents at birth or within the first few months of life. This condition often was diagnosed with reduced spontaneous movements due to progressive joint contractures (1). Progressive skin thickening, short stature, gingival hypertrophy, hyper-pigmented patches on bony prominences and fleshy nodules (particularly in the perianal region) are the most clinical manifestations. Osteopenia may lead to increased susceptibility to bone fractures. Affected children are susceptible to frequent infections and/or intractable diarrhea due to protein-losing enteropathy. Most of them will die in infancy from organ failure (2).

ZLS is an extremely rare craniofacial malformation syndrome characterized by oral specific feature of diffuse gingival fibromatosis in early childhood (3, 4). Its prevalence was reported less than 1/1000000(5). It may be presented with several signs composed of gingival fibromatosis, seizure, and dysplastic or absent fingernails, hypoplasia of the distal phalanges, scoliosis, abnormal fingers, hepatomegaly/splenomegaly, hypertrichosis, hirsutism and abnormalities in nose and/or ears anatomy(6). Colpocephaly, hemi-vertebra, polydactyly, segmental hyper pigmentation, and hemi hyperplasia, thus expanding the phenotypic spectrum of the disease are the other reported signs related to the syndrome in literatures (7, 8). Cardiovascular and gastrointestinal problems were reported, too.

Other manifestations include abnormalities of dental, oral, and craniofacial, extremities, solid organs and also nervous system could be seen. Most patients suffer from aesthetic problems and functional disorders owing to hereditary gingival fibromatosis (9).

Researchers mentioned facial and extremities disorders involved ear thickness with cartilage softness, nose prominence, gingival overgrowth, nails aplasia or hypoplasia and type B brachydactyly. Other studies reported hirsutism, mental disability, and visceral organ involvement (10). A wide range of clinical manifestations were reported. In respect of age some cases were child while other were adult at the time of diagnosis (8, 11, 12). Mental retardation were reported in some cases while others had an IQ score in normal range (7, 12, 13). One of the important aspect of ZLS is differential diagnosis. Gingival fibromatosis (GF) is a sporadic condition that may be associated with syndromes. In this condition teeth might be embedded in hyperplastic gingiva (14). Knowing about differential diagnosis of gingival fibromatosis could be helpful for clinicians to differentiate ZLS from other probable diagnosis (15, 16). Genetic role in ZLS was also investigated and proved as a probable etiology of ZLS (17). In most cases, Laband syndrome is inherited by an autosomal dominant trait. However, some evidences of autosomal recessive inheritance have also been reported (10). In severe cases, surgical removal of the hyperplasic fibrous tissue may be required to expose embedded teeth. Surgical excision is a selective procedure for patients with special needs (5). Although the syndrome is not life-threatening, the prognosis is related to the severity of manifestations.

We report an 18 months old female patient with an overlapping feature of ZLS and ISH. Literature review was carried out due to update knowledge on these syndromes and try to shed more light on its clinical manifestations. She presented a severe generalized gingival hyperplasia and embedding of the deciduous teeth. In spite of other cases which have been reported by medical specialties, it is reported by an oral medicine specialist and an oro-maxillo-facial surgeon. This case considering gingival fibromatosis as a diagnostic mile stone, has been reported. Also a review of literatures was done to provide a spectrum of related manifestations and compare with this report. These data would help clinicians to provide proper diagnosis and distinguish similar differential diagnosis.

An 18-month-old female patient was referred to an oral medicine specialist due to gingival enlargement. The chief complaint was an excessive gingival overgrowth of the anterior region of the mouth, which had covered all deciduous teeth since eight months ago (Fig. 1).

The patient was the unique child of a 25-year-old woman and her healthy 38-year-old husband with no history of consanguinity. The other old sibling died at eight months old because of excessive diarrhea with no definite diagnosis. Familial history and pregnancy history were unremarkable. Her parents appeared healthy. According to the parents’ information, they had a boy who died, when he was 6-month-old. He had the same knee skin lesions. Her birth history illustrated that she was born at full term (39 weeks) via normal spontaneous vaginal delivery following an uncomplicated and uneventful pregnancy. During the first four months of life, the patient’s growth and development were assessed at regular visits and matched with her age.

In clinical examination, short stature, hypoplasia of the distal phalanges, scoliosis, hepatosplenomegaly, recurrent chest infections, and well-demarcated, blanchable, violaceous patches over the back was seen. Diffused papulo-nodular lesions were observed on her ear helixes and neck (Fig. 1). The firm lesions resemble a pearl shape on the nose. The skin of the whole body, especially in the neck, back, and lumbar, was covered with multiple papulo-nodular lesions. Flexion contracture was seen in the hands and knee joints (Fig. 2). A genetics review at 20 months of age showed that he was delayed. She could not sit, stand, or walk even on all fours and could only speak a few words. She was referred for an intelligence quotient (IQ) test. It was in the normal range. Hearing loss (based on Transient-evoked otoacoustic emission (TEOAE) and OSM tests) was absent. Mental retardation was not observed. More detail is noted in Table 1.

Table 1

Clinical manifestations
Manifestations Lesions	Body skin	Mental retardation	Gastrointestinal system	Head and face	Oral	Neck	Extremities and skeletal system
Type of involvements and locations	Multiple popular (on neck, back and lumber) Populonodular (body skin)	No	Diarrhea but no specific disease	Multiple rashes (around nose) Popular firm lesions resembling pearl-shape, keratolytic psoriasis (ear helix) Wide nasal ridge	lower lip protrusion alveolar ridge swelling open mouth embedded erupted teeth under gingiva	plaque –like lesions with non-smooth surface and erythematous base (mostly on posterior site)	Three main palmar lines (absence of other palmar lines) Lumber deformity halluces hypotonic myopathy joint stiffness dysarthria

Head and neck examination revealed facial abnormalities composed of saddle nose, bilateral nodules around the nasal alae with some of the papules coalescing into small plaques, especially over the ears, swollen lips, hirsutism, hypertelorism, and coarse hair (Figs. 1 and 3).

Intraoral examination revealed maxillofacial deformity, an extensive pale pink firm enlargement of gingiva involving the maxillary and the mandibular arches, alveolar ridge swelling, non-plaque induced gingival diseases, and conditions, and anterior open bite. Embedded maxillary and mandibular anterior teeth were discovered after palpation that was completely covered with gingiva fibromatosis. This growth had a monotonous base with the lobular surface. The palate was free of any lesions (Fig. 3).

Maxillofacial manifestations were absent till six months. Skin lesions of the ear and gingival enlargement had worsened gradually during the recent six months. At the age of 18 months, she was referred to an oral medicine specialist with the chief complaint of feeding and breathing difficulties due to gingival overgrowth.

A review of her system showed a limited range of motion of upper and lower limbs and muscle weakness. Hepatosplenomegaly was confirmed in ultrasonography. She had two symmetrical skin macules around both knees. The cardiac evaluation was normal. Head and neck MRI with and without contrast was reported normal, too (Fig. 4). The patient was admitted several times to investigate muscle hypotonia, excessive diarrhea, and diagnostic workup. Laboratory tests were in the normal range except for mild leukocytosis, anemia, and CRP = 3+. The radiographic examination also was demonstrated in Fig. 4.

Clinical documents usually are sufficient to diagnose ZLS, while making a diagnosis of gingival fibromatosis in most cases is achieved with plain oral biopsy and confirmed after microscopic evaluation. An incisional lower lip and gingiva biopsy was performed and sent for evaluation. The microscopic assessment showed hyperplastic squamous epithelium overlying a collagenized fibrous stroma with sparse lymphocytic infiltration. These findings were attributed to gingival fibromatosis.

after one year, head and neck papules get worsen, specially on the posterior area of neck. (Fig. 5). Body rigidity get worsen, too. she could not able to sit on the dental chair or use the hands for eating at age 2/5 years old. No mental problem was seen and she was able to speak like a normal 2 years old child.

Lip prominence relapsed 8 months after surgery. Teeth eruption was normal but poor oral hygiene due to the hard accessibility to the mouth was seen. These new presentations seemed to be related to the systemic condition control.

ZLS has overlapping manifestations with some disorders, which include: FHEIG syndrome (characterized by facial dysmorphism, hypertrichosis, epilepsy, intellectual disability/developmental delay, and gingival overgrowth). Diagnostic criteria for FHEIG syndrome did not fulfil in this case. Therefore it was put away. Dermatologists suggested ISH as the first diagnosis based on skin lesions on the peri-nasal and auricle (18). This syndrome is diagnosed by the deposition of amorphous hyaline material in different solid organs. Considering the severity of disorders gastrointestinal tract, cardiac, adrenals, spleen, thyroid, and adrenal glands may be involved. Ultimately leading to multi-organ failure as a cause of death (19). Based on the findings, the patient was referred for genetic evaluation.

Genetic counseling proposed "Snijders Blok-Campeau syndrome" (autosomal dominant) and mutation in Exon 1 in CHD3 gene. Snijders Blok-Campeau syndrome has neurological symptoms, orofacial structures, and musculoskeletal system involvement but not skin. Other manifestations are hypotonia, hearing loss, widely spaced eyes, mid-face hypoplasia, low-set ears, broad nasal base, joint laxity, and broad forehead (20). Findings were not matched with this disorder.

Despite familial aggregation, different inheritance patterns have been registered. To the best of our knowledge, the most confirmed ZLS follows an autosomal dominant inheritance, usually resulting from a de novo mutation (21, 22). But the common trait of ISH is autosomal recessive. Nevertheless, the phenotype of another gene candidate of KDSR was refused (1).

This is similar to ISH regarding age, skin manifestations, and oro-facial expressions, especially lower lip prominence. It usually occurs due to amorphous hyaline material deposition. Considering the presence of hyperpigmentation on both knees, it was not compatible with classic hyperpigmentation of ISH. Classic hyperpigmentation of ISH is focused on metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints and malleoli.

At two years of age, he underwent a gingivectomy for her gingival fibromatosis under general anesthesia by an oral and maxillofacial surgeon (Fig. 6). At six months follow-up after surgery, the gingival fibromatosis recurred. She had no serious problem with eating or breathing with this alliance.

In other words, some diverse clinical presentations appear to be a multitude of diseases manifesting as asymptomatic carriers among the siblings and relatives of rare cases. It's worth mentioning that the genetic carriers (with the late manifestation of the disorders) are more frequent than the subjects with the severe type of ISH and ZLS.

To the best of our knowledge, she is the second case of ZLS-related signs who was diagnosed at the age of under 2. In spite of other cases that pediatrics or other medical specialists have reported, this case considering gingival fibromatosis enlargement as a diagnostic milestone has been reported by oral medicine specialists and oral and maxillofacial surgeons. We wish to note that the confusing different manifestations of children with ISH or ZLS have made pediatricians and clinicians underestimate the frequency of such slowly progressing but serious heritable conditions with a devastating outcome (Table 2).

Table 2

comparison the case and three probable diagnosis
Syndromes
Syndromes	Neurology	Orofacial	Musculoskeletal system	Skin	organ involvement
Snijders Blok-Campeau syndrome	Hypotonia Widened CSF spaces (MRI) Neonatal feeding problems Microcephaly Delayed myelination Prominent extra-axial space Seizures intellectual disability macrocephaly impaired speech (Delay) and language Hearing Loss Cerebral visual impairment	Widely spaced eyes Frontal bossing Full Cheeks Peri-orbital fullness epicanthal folds narrow palpebral fissures deep-set eyes more prominent supra-orbital ridge Mid-face hypoplasia low-set ears (posteriorly rotated or simple with thick helices) broad nasal base prominent nose bifid nasal tip broad nasal tip pointy chin sparse eyebrows Hypermetropia Strabismus Astigmatism Myopia Absent teeth Thin upper lip	Joint laxity (generalized and/or local) High forehead Broad forehead Leg deformity prominent forehead		males Genital abnormalities Patent ductus arteriosus Ventricular septal defect Atrial septal defect Hernia (inguinal, umbilical, hiatal)
Zimmermann-Laband syndrome	Hemi-hyperplasia Seizures learning disability facial palsy	atypical retinitis pigmentosa thick eyebrows hypertelorism large fleshy nose bulbous soft nose thick floppy ears no eruption of primary teeth hearing loss bilateral developmental cataract posteriorly rotated ears pit on ear helix wide nasal bridge mildly hypoplastic nostrils malformed external ear lobes massive gingival overgrowth short philtrum thin upper lip gingival fibromatosis Macroglossia supernumerary teeth wide fissures of tounge deep fissures of tounge unable to close mouth Anterior end to-end bite symmetric soft tissue swelling of the palate	polydactyly vertebral defects hypoplasia / aplastic of distal phalanges hyperextensibility of joints aplastic/hypoplastic nails hypoplasia of the distal phalanges joint hypermobility short stubby fingers absence of nails myoclonus	Hyperpigmentation mild hirsutism	hepatosplenomegaly
Infantile systemic hyalinosis	progressive ataxia spasticity neurodevelopmental regression cerebellar atrophy	gingival hypertrophy Labial Hypertrophy buccal hypertrophy inability to open mouth	synovial thickness in joint hypertonia joint contractures knee pain limited range of motion in extremities and weakness short limbs and neck torticollis Osteoporosis Stunted growth osteolytic bone lesions	papulonodular skin lesions papuloerythematous rash large subcutaneous tumors Hyperpigmentation generalized stiff skin edematous skin	protein losing enteropathy diarrhea rectal prolapse lymphangiectasia recurrent infections thyroid dysfunction
Our case	No	Multiple rashes (around nose) Popular firm lesions resembling pearl-shape, keratolytic psoriasis (ear helix) Wide nasal ridge lower lip protrusion alveolar ridge swelling open mouth embedded erupted teeth under gingiva plaque –like lesions with non-smooth surface and erythematous base (mostly on posterior site	Three main palmar lines (absence of other palmar lines) Lumber deformity halluces hypotonic myopathy joint stiffness dysarthria	Multiple popular (on neck, back and lumber) Populonodular (body skin)	Diarrhea but no specific disease

Genetic tests for the intermediary group of syndromes often yielded undesirable results. Therefore such a misleading parameter added another burden for these families because of the unexplained long-term presentations and slowly progressing genetically programmed abnormalities.

In conclusion, this case falls between ISH and ZLS. She demonstrated some presentations of two syndromes. Genetic analysis was not entirely matched with the two syndromes mentioned above. Although ZLS remains an enigma for specialists to date because of its ambiguous presentations, the timely diagnosis could be crucial for prognosis and prevention of severe further surcharge. Dentists could have an essential role in diagnosing rare disorders like ZLS.

Zimmermann-Laband Syndrome (ZLS)

infantile systemic hyalinosis (ISH)

Gingival fibromatosis (GF)

transient-evoked otoacoustic emission (TEOAE)

metacarpophalangeal (MCP)

proximal inter phalangeal (PIP)

Ethics approval and consent to participate

Written consent for publishing this information was obtained from the parents and proof of consent to publish can be requested at any time.

Consent for publication

Informed consent to publish all identifying information was obtained from the parents of the patient.

Availability of data and materials

The datasets are available on reasonable request to corresponding author.

Competing interests

The authors declare that there is no conflict of interest.

Funding

There is no source of funding.

Authors' contributions

FO: writing and revision of the manuscript, patient treatment and follow-up

AN: patient treatment and follow-up, revision of the manuscript

MHAK: patient treatment and follow-up, revision of the manuscript

MMDB: writing of the manuscript, patient follow-up

Acknowledgments

we would like to thank the parent(s) of the patient for their full cooperation.

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No competing interests reported.

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Zimmermanne Laband syndrome and infantile systemic hyalinosis: an enigma with two separate terms with overlapping features: case report and literature review

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