Neonatal Schwartz-Jampel syndrome type II: a rare case of peripheral origin of neonatal hypertonia
- 1 Bharati Vidyapeeth University, Pune, Maharashtra, India
- 2 Neonatology, Bharati Vidyapeeth University, Pune, Maharashtra, India
- Correspondence to Dr Reema Garegrat; coolreem18@yahoo.com
Abstract
Neonatal Schwartz-Jampel syndrome type II is a rare and severe form of genetic disorder. Different from the classical appearance in infancy, neonatal presentation involves respiratory and feeding difficulties, along with characteristic pursed appearance of the mouth, myotonia, skeletal dysplasia and severe fatal hyperthermia. The clinical spectrum of this syndrome is so wide that it easily baffles with more common differentials. In this case report, a neonate born to third-degree consanguineous marriage with previous two abortions presented with respiratory difficulty, severe hyperthermia and feeding difficulty, which were daunting challenges to manage due to being refractory to standard line of management. Severe myotonia and gross dysmorphism were challenging dots to connect. Targeted exome sequencing was a ray of hope, which revealed homozygous mutation in the leukaemia inhibitory factor receptor gene on chromosome 5p13, confirming the genetic diagnosis for a fairly common spectrum of symptoms. The neonate later developed pneumoperitoneum and succumbed to underlying severe neonatal illness.
Background
Schwartz-Jampel syndrome (SJS) is a rare autosomal recessive disorder characterised by the presence of myotonia with a mask-like face and skeletal dysplasia with intrauterine growth retardation. As per the age of manifestation, this syndrome is classified into two types: classical type, observed in late infancy or childhood, and rarer type, a severe form usually presenting in neonatal period. This syndrome presents at birth usually with facial dysmorphism, skeletal abnormalities, and respiratory and feeding difficulties.1 To date, there are around 18–20 published cases of this syndrome worldwide. Of the published cases, most of them had either infantile or early childhood presentation. In this case report, a rarer and more severe neonatal form is reported.
Case presentation
This case was a female baby born to a multigravida mother aged 24 years, with previous two abortions and third-degree consanguineous marriage. The first conception was antenatally diagnosed with skeletal dysplasia (short femur and humerus), for which medical termination of pregnancy was opted, and the second one was a blighted ovum. Karyotyping of both parents was reported to be normal. The pedigree chart of the family is shown in figure 1. In the present pregnancy, the antenatal ultrasound was suggestive of severe intrauterine growth restriction and skeletal dysplasia (in the form of short femur and humerus). The baby was delivered at term gestation by emergency caesarean section due to severe oligohydramnios, intrauterine growth restriction and fetal distress. The baby cried immediately after birth, developed respiratory distress and was admitted in the neonatal intensive care unit.
Pedigree chart of the family depicting third-degree consanguineous marriage with first conception aborted and second being blighted ovum.
Born at 38 weeks, the birth weight was 1705 g (<10th centile), the head circumference was 29 cm (3rd centile) and the length was 44 cm (<10th centile). Significant dysmorphism was noted at birth, in the form of characteristic pursed appearance of the mouth mainly during crying, short palpebral fissure, short limbs with bowing of both lower limbs (especially tibia), overlapping of fingers and toes, limited extension of elbow joint (elbow joint contracture) and severe hypertonia slowly emerging over the first 72 hours (figure 2A,B). The baby was initially managed with non-invasive respiratory support; chest X-ray suggested upper lobe collapse/consolidation and was given a course of antibiotic (piperacillin and tazobactam) for possible congenital pneumonia. However, no clinical improvement was noted overtime. In light of the COVID-19 pandemic, the mother tested positive for COVID-19 by reverse transcription PCR; however, the baby tested negative.
Detailed description of the clinical features. (A) Note shortening and bowing of the long limbs (white arrow) with overlapping of the fingers and toes (arrowheads). (B) Infantogram: showing short femur and humerus (double line arrow), bowing of tibia (white arrow) and short and thick bones with large metaphyses. The angulations of the femur and tibia are sharp with marked cortical thickening at the diaphyseal concavity (solid arrow). (C) Classical pursed appearance of lips and mouth (blue arrows). (D) Chest X-ray showing right-side extensive consolidation. (E) X-ray of the abdomen showing perforation with gas under diaphragm (single line arrow).
The baby had multiple episodes of severe myotonia, unexplained hyperthermia (up to 105°F) and peculiar facial appearance (pursed appearance of the mouth) within 48 hours of life (figure 2C). The baby was initially managed with phenobarbitone in suspicion for possible seizure-like episode. However, later on, frequent similar breakthrough episodes were noted; multiple antiepileptic medications were tried, with most being ineffective in aborting these episodes. Of all, carbamazepine resulted in some clinical improvement, that too with no complete resolution of symptoms.
The baby continued to have repeated episodes of severe unexplained hyperthermia with severe myotonia, generalised hypertonia, repeated episodes of aspiration with poor swallow and gag reflex requiring prolonged nasogastric tube feeding in the span of 37 days of hospitalisation.
Investigations
In light of clinical features suggesting syndromic appearance, detailed work-up was done before the baby succumbed to underlying illness. Radiological features suggested bowing of the long bones, particularly lower limbs with diaphyseal concavity of the ribs and long bones and shortening of both radius and humerus (figure 2B).
Medical genetic consultants advised for electromyography (EMG) and nerve conduction velocity study for episodic myotonia with characteristic pursed appearance of the mouth and severe hyperthermia, which were reported to be within normal limits.
Twenty-four-hour video electroencephalogram (EEG) revealed normal background activity with no epileptiform discharges, and MRI of the brain done at 15 days of life was also within normal limits.
With strong suspicion for rarer possible syndromes, targeted gene sequencing done revealed a homozygous non-sense variation in exon 7 of the LIFR gene (leukaemia inhibitory factor receptor gene), which results in stop codon and premature truncation of the protein at codon 278, thereby leading to a rare diagnosis of neonatal SJS (type II), also known as Stuve-Wiedemann syndrome. Parents were counselled about the disease and the poor long-term outcomes reported until now. They were offered genetic and prenatal counselling as well for future pregnancies.
Differential diagnosis
Persistent hypertonia in a neonate slowly emerging after birth is a diagnostic challenge. It is broadly classified as central or peripheral in origin. Central causes of hypertonia were less likely as there was no significant history of birth asphyxia, no signs of upper motor neuron lesion, no encephalopathy, negative glabellar tap and doubtful seizure-like episodes refractory to antiepileptics with normal EEG and MRI findings.
One of the common causes of peripheral neonatal hypertonia in low-income to middle-income countries is neonatal tetanus. However, the mother was adequately vaccinated and adequate standard of cord care was given at birth.
Considering the other peripheral causes of neonatal hypertonia, what stood out against all other differentials was SJS with characteristic dysmorphism, skeletal dysplasia and hypertonia, resembling exactly the present case. However, characteristic EMG findings as seen in SJS were absent. Hence, based on the clinical findings, possibility of peripheral hypertonia due to SJS was highly suggestive.
Outcome and follow-up
The baby had increasing respiratory distress, feed intolerance and abdomen distention at 32 days of life. Blood work-up revealed possible late-onset sepsis, and the culture grew Escherichia coli organism sensitive to carbapenems. X-ray of the abdomen revealed distended bowel loops, with serial X-ray of the abdomen revealing pneumoperitoneum (NEC (necrotising enterocolitis) stage IIIB, according to Modified Bells Staging) on 37th day of life (figure 2D,E). The baby was treated with antibiotics, inotropic support and blood products. The parents were counselled about the need for surgical intervention for NEC and about the genetic disease and its poor outcome (figure 3). After multiple discussions of parents with the multidisciplinary team, the parents opted for conservative management in view of dismal chances of intact survival and long-term outcome. The baby succumbed to underlying illness on day 39 of life.
Details of targeted gene sequence report of the baby investigated during the hospital stay.
Discussion
In 1962, the first case of SJS was identified by Oscar Schwartz and Robert S. Jampel as congenital blepharophimosis with characteristic unique generalised myotonia in a Caucasian girl. Later, similar phenotypic features were noted in her male sibling born after 3 years.2 Later on, many such cases with similar characteristic phenotypic features were diagnosed under SJS, and until now, a total of around 100 cases have been identified worldwide.
SJS is classified into two major types. Type I is further classified as IA, which appears in late infancy or childhood, and IB, which appears in neonatal period and is clinically more severe, although compatible with life and even long-term survival. Type I SJS is due to mutation in the HSPG2 gene on chromosome 1p34-36.1 which codes for perlecan proteoglycan.3 Due to mutation, abnormally functioning perlecan proteins lead to deficiency of acetylcholinesterase, an enzyme required for breakdown of acetylcholine, thereby leading to severe muscular contraction.4
Type II is similar to type IB, apparent at birth, severe in nature and mapped to LIFR gene on chromosome 5p13.1. All cardinal features of type II were evident in our case with confirmed genetic report. A high infant mortality has been reported in previous cases similar to the present case with rare long-term survivals.5
Prenatal diagnosis of this syndrome involves mid-trimester scans to look for bowing of the long bones, a non-specific finding, and this narrow down to three likely differentials which include campomelic dysplasia, kyphomelic dysplasia and SJS. Based on the absence of scapular and pelvic abnormality and rhizomelic mesomelic shortening of limbs, campomelic dysplasia and kyphomelic dysplasia can be ruled out, respectively. On the contrary, SJS has characteristically marked thickening at the diaphyseal concavity, which helps in prenatal diagnosis. However, for termination of pregnancy, accurate prenatal diagnosis is required for which prenatal whole exome sequencing using DNA extracted from chorionic villi or amniocyte is the gold standard. In the SJS depending on the type, either HSPG gene mutation or LIFR gene mutation can confirm the diagnosis and helps in counselling the parents for prognosis. In this case, their first conception was antenatally diagnosed to have skeletal dysplasia and underwent medical termination. For the third conception as well, antenatal scans revealed skeletal dysplasia, and for further testing, the parents underwent karyotyping which was normal. However, they did not seek prenatal whole exome sequencing due to lack of awareness and possible financial constraints.6 7
Postnatal diagnosis is made by characteristic phenotypic features with supportive blood chemistry and confirmed by EMG and exome sequencing. In this case, we found high creatine phosphokinase (CPK) N-acetyl-cysteine activity similar to many previously reported cases with high CPK levels.8 EMG typically shows high-frequency discharges more constant in frequency than those of classical myotonia with the absence of waxing and waning in amplitude and frequency. However, in the present case, EMG done twice was reported to be normal. Previous case reports like Beighton et al and Fowler et al 9 showed characteristic EMG findings; however, Ferguson et al 10 did not show similar findings. Definitive diagnosis is by targeted exome sequencing, which can delineate the molecular basis of the diagnosis as mentioned above and classify the SJS as type I or type II. Other less common test includes muscle biopsy, muscle MRI and electron microscopy.
The most unique clinical presentation was the presence of severe hyperthermia (maximum temperature recorded was 105°F), which stands apart from the usual clinical features seen in the neonatal form of SJS. Usual age of presentation is in infancy with predominant musculoskeletal symptoms and signs; SJS type II stands out unique in terms of its fatal neonatal presentation with predominantly respiratory symptoms and feeding intolerance.
Diagnosis is generally made by classical physical phenotypes and aided with EMG and genetic confirmation. Two close mimics of SJS are Freeman-Sheldon syndrome with whistling face, puckered lips, microstomia, long philtrum and dimpled chin. There is ulnar deviation of the hand, causing windmill vane configuration. Marden-Walker syndrome is associated with immobile facies, blepharophimosis, mental retardation, congenital joint contractures and failure to thrive.11
Treatment mainly involves symptomatic support; however, a poor response to benzodiazepines and diphenylhydantoin has been noted. Some clinical benefits of carbamazepine have been noted in previous studies, particularly if started early in the course.12 Hence, any baby born to a consanguineous marriage with classical phenotype as our reported case should thoroughly be investigated under various differentials of neonatal hypertonia. The severe manifestations along with poor long-term outcomes make it critical to offer prenatal counselling and diagnosis for affected families using prenatal whole exome sequencing.
Learning points
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Subacute onset of neonatal hypertonia is mostly central in origin, but rare peripheral causes do exist with some having possible treatment.
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Peripheral hypertonia with characteristic dysmorphism, unexplained hyperthermia and skeletal dysplasia is diagnostic of Schwartz-Jampel syndrome (SJS) type II.
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Early involvement of paediatric neurologist and clinical geneticist in difficult cases of neonatal hypertonia helps in timely diagnosis and intervention.
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Clinical benefit of carbamazepine if started early has been seen in some cases of neonatal SJS.
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The gold standard test for diagnosing SJS is targeted gene sequence; however, clinically subacute onset of hypertonia with antenatal diagnosis of skeletal dysplasia is virtually diagnostic of SJS.
Ethics statements
Acknowledgments
The authors thank Dr Chaitanya Datar for his insights into the genetic diagnosis and Dr Kavita Shrivastava for the joint management and care along with a timely diagnosis.
Footnotes
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Contributors AV and RG designed, drafted and revised the article. NB and PS revised it critically for important intellectual content. All authors contributed to the final approval of the version to be published.
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Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
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Competing interests None declared.
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Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.
References
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