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 Table of Contents  
CASE REPORT
Year : 2021  |  Volume : 1  |  Issue : 4  |  Page : 244-246

Neonatal osteosclerotic bone dysplasia (Raine syndrome)


Department of Neonatology, Niloufer Hospital, Osmania Medical College, Hyderabad, Telangana, India

Date of Submission30-May-2021
Date of Decision12-Nov-2021
Date of Acceptance13-Nov-2021
Date of Web Publication29-Nov-2021

Correspondence Address:
Dr. Swapna Lingaldinna
HNo. - 16-1-18/27, 1st Floor, Sri Krishna Nilayam, Saidabad Colony, Hyderabad - 500 059, Telangana
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ipcares.ipcares_157_21

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  Abstract 

Background: Raine syndrome is a rare autosomal recessive neonatal osteosclerotic bone dysplasia caused due to mutations in the FAM20C gene. It has an early and aggressive onset which often results in death in the first few weeks of life, although there have been cases of patients surviving into childhood. Clinical Description: We describe the case of a neonate girl born with microcephaly, proptosis, triangular mouth, depressed flat nasal bridge, mid-face hypoplasia, low set ears, high-arched palate, and a wide-open anterior fontanelle. Based on the clinical phenotype, the differentials considered were a congenital infection and Crouzon syndrome. Management: Infantogram revealed generalized osteosclerosis. Based on the radiological phenotype, the differentials considered include Thanatophoric dysplasia, osteopetrosis, and Achondroplasia. Search for concealed anomalies revealed dysmorphic features in the brain and kidneys. The clinical exome demonstrated a heterozygous missense and heterozygous nonsense variant in exon-7 of the FAM20C gene, which established the diagnosis of Raine syndrome. Conclusion: Genetic analysis based on phenotype can aid in the early diagnosis of dysmorphic children and help in instituting appropriate management

Keywords: Dysmorphic features, FAM20C gene, intracranial calcifications, osteosclerosis


How to cite this article:
Girigiri TK, Reddy T, Madireddy A, Lingaldinna S. Neonatal osteosclerotic bone dysplasia (Raine syndrome). Indian Pediatr Case Rep 2021;1:244-6

How to cite this URL:
Girigiri TK, Reddy T, Madireddy A, Lingaldinna S. Neonatal osteosclerotic bone dysplasia (Raine syndrome). Indian Pediatr Case Rep [serial online] 2021 [cited 2022 Jan 20];1:244-6. Available from: http://www.ipcares.org/text.asp?2021/1/4/244/331366

Raine syndrome is a rare autosomal recessive neonatal osteosclerotic bone dysplasia due to a mutation in the FAM20C gene. The prevalence is <1 per million. This condition was included in the Online Mendelian Inheritance in Man as “Osteomalacia, sclerosing, with cerebral calcification” in 1986. Three years later, Raine et al.[1] expanded the phenotype to include microcephaly, exophthalmos, hypoplastic nose, low-set ears, gum hypertrophy, cleft palate/uvula, severe midface hypoplasia with choanal atresia, generalized osteosclerosis, and calcification on brain imaging.

We present this neonate with the characteristic phenotype of Raine syndrome corroborated with a pathogenic genetic mutation. The case is presented due to its rarity (incidence 1 per million) and also to highlight the approach a clinician should use in neonatal with craniofacial dysmorphism and generalized osteosclerosis.


  Clinical Description Top


A 3-day-old girl was brought to us with parental concerns regarding unusual features. She was born of a third-degree consanguineous marriage and was third in birth order. The delivery was conducted at 36 weeks of gestation by cesarean section for oligohydramnios. The birth weight was 2800 g, and there were no perinatal complications. There was no history of any antenatal maternal illnesses, or exposure to teratogens. The family history was not contributory.

At admission, the baby was euthermic with a pulse rate of 125/min (min), respiratory rate of 52/min, and normal capillary filling time. The growth parameters were: Weight 2.8 kg [−1.22 standard deviations (SD)]; length 46 cm (−2.3 SD); and head circumference 30 cm (−3.8 SD). The baby had overt craniofacial dysmorphism with proptosis, microcephaly, wide-open anterior fontanelle, flat and broad nasal bridge, low set ears, midfacial hypoplasia, high-arched palate, and a triangular-shaped mouth [Figure 1]. There was no choanal atresia. The spine was normal, and there were no arthrogryposis or limb and trunk anomalies. The respiratory, cardiovascular, abdominal (including genitalia), and neurological examination was normal. Fundus and hearing (otoacoustic emission) evaluations were normal. Based on the presence of microcephaly and craniofacial anomalies, the differential diagnoses considered were a craniosynostotic syndrome (possibly Crouzon) or a congenital infection.
Figure 1: Newborn with microcephaly, exophthalmos, depressed nasal bridge, low set ears, and inverted U-shaped mouth

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Management and outcome

The TORCH profile for congenital infections was negative. Additional tests were done to rule out concealed congenital anomalies. Ultrasonography of the brain detected bilateral periventricular hyperintensities, and that of the abdomen bilateral hydronephrosis. Computerized tomography scan of the brain delineated additional anatomical abnormalities; bilateral symmetrical calcifications (in the periventricular and capsule-ganglionic regions, dentate nuclei, and tentorium), proptosis, frontal bossing, and absent nasal bones [Figure 2]. The two-dimensional echocardiograph was normal. An infantogram (ordered to detect additional skeletal anomalies) revealed generalized osteosclerosis. There were no fractures or periosteal bone formation. Based on the clinical and radiological phenotype, the differentials were narrowed down to osteopetrosis, thanatophoric dysplasia, and achondroplasia.
Figure 2: Infantogram with generalized osteosclerosis

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Normal blood counts ruled out cytopenias that are seen in osteopetrosis. Serum electrolytes and kidney function tests were normal. A literature search (Google Scholar and PubMed) for cases of neonatal osteosclerosis and the identified dysmorphic features led us to consider another differential, Raine syndrome. A genetic consultation was taken, and next-generation sequencing (NGS) was advised (as per the protocol of an infant with multiple congenital anomalies). This revealed a compound heterozygous mutations involving the FAM20C gene in Chromosome 7p22. The first was a heterozygous nonsense variant in exon 7 of the FAM20C gene (chr7:296641C>G). This has been reported to results in a stop codon and premature truncation of the protein at codon 425 (p. Tyr425Ter; ENST00000313766.5). It is a pathogenic variant. A heterozygous missense variant mutation was identified in exon 7 of the FAM20C gene (chr7:296717G>A). This results in amino acid substitution of Asparagine for Aspartic acid at codon 451 (p. Asp451Asn; ENST00000313766.5) and has been observed to lie in the Golgi casein kinase, C-terminal, Fam20 domain of the FAM20C protein. It has previously been reported in Raine syndrome or neonatal osteosclerotic bone dysplasia. Thus, our clinical suspicions were confirmed. The parents were given genetic counseling and the patient kept under follow up. Subsequently, she developed generalized epilepsy, developmental delay, a humerus fracture following a trivial and expired at 2 years of age after an acute illness with respiratory distress and seizures. Having a genetic diagnosis helped the family understand the nature and course of her illness.


  Discussion Top


This case highlights the approach that we used once we narrowed down on salient clinical clues; neonatal onset, microcephaly, absent nasal bones, and generalized osteosclerosis. A literature search gave us a clinical differential and NGS confirmed the genotype. However, we were unable to get segregation analysis, as the parents were not planning any further pregnancies.

Raine syndrome is a rare disorder that arises due to biallelic loss-of-function mutations of the FAM20C gene located on chromosome 7p22.3. Tagliabracci et al.[2] determined that the FAM20C gene phosphorylates caseins and other proteins involved in the biomineralization of bone like small integrin-binding ligand N-linked glycoproteins (SIBLINGs). Mutations occurring at this locus affects FAM20C kinase activity and secretion and results in abnormal phosphorylation of SINBLINGs and the typical biomineralization phenotype. Hung et al.[3] reported that all lethal pathogenic variants were situated close to functional protein regions (catalytic, dimerization, and glycosylation sites), whereas the healthy homozygotes had polymorphic changes detected in sites furthest away from the catalytic pocket or functional regions. Prenatal diagnosis is possible and has been reported in three fetuses with typical features; intracranial calcifications, hypoplastic nose, midfacial hypoplasia, ectopic renal and hepatic calcifications, and osteosclerosis.[4]

The life span of affected individuals is variable, ranging from early infantile deaths to survival into adolescence. Most patients die of severe respiratory distress during the neonatal period, due to pulmonary hypoplasia and choanal atresia/stenosis. Nonlethal variants have craniofacial, thoracic and limb abnormalities along with osteosclerosis, hypophosphatemic rickets, and neurological disorders such as seizures and development delay.



Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the legal guardian has given his consent for images and other clinical information to be reported in the journal. The guardian understands that names and initials will not be published and due efforts will be made to conceal patient identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Whyte MP, McAlister WH, Fallon MD, et al. Raine syndrome (OMIM #259775), caused by fam20c mutation, is congenital sclerosing osteomalacia with cerebral calcification (OMIM 259660). J Bone Miner Res 2017;32:757-69.  Back to cited text no. 1
    
2.
Tagliabracci VS, Engel JL, Wen J, et al. Secreted kinase phosphorylates extracellular proteins that regulate biomineralization. Science 2012;336:1150-3.  Back to cited text no. 2
    
3.
Hung CY, Rodriguez M, Roberts A, et al. A novel FAM20C mutation causes a rare form of neonatal lethal Raine syndrome. Am J Med Genet A 2019;179:1866-71.  Back to cited text no. 3
    
4.
El-Dessouky SH, Abdel-Hamid MS, Abdel-Ghafar SF, et al. Raine syndrome: Prenatal diagnosis based on recognizable fetal facial features and characteristic intracranial calcification. Prenat Diagn 2020;40:1578-97.  Back to cited text no. 4
    


    Figures

  [Figure 1], [Figure 2]



 

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