Stuve-Wiedemann Syndrome
A number sign (#) is used with this entry because of evidence that Stuve-Wiedemann syndrome (STWS), also known as neonatal Schwartz-Jampel syndrome type 2 (SJS2), is caused by mutation in the leukemia inhibitory factor receptor gene (LIFR; 151443) on chromosome 5p13.
DescriptionStuve-Wiedemann syndrome is an autosomal recessive disorder characterized by bowing of the long bones and other skeletal anomalies, episodic hyperthermia, and respiratory and feeding distress usually resulting in early death (Dagoneau et al., 2004).
See also 'classic' Schwartz-Jampel syndrome type 1 (SJS1; 255800), a phenotypically similar but genetically distinct disorder caused by mutation in the HSPG2 gene (142461) on chromosome 1p36.
Clinical FeaturesStuve and Wiedemann (1971) reported 2 sisters and a first-cousin male with congenital bowing of the long bones. Other features included short stature, camptodactyly with ulnar deviation, and contractures of the elbows and fingers. Radiographically, the long bones were short and thick with large metaphyses. Although the clavicles were normal, there was a broad coracoid process bilaterally, long scapulae, and relatively thin ribs. The pubic and ischial bones were broad and the ilia relatively small. One patient died after 10 days of life from respiratory insufficiency with apnea; her sister developed hyperthermia with temperatures as high as 41 degrees centigrade and died on day 5 of life. The male first cousin to these 2 girls had identical congenital flexion contractures of the fingers and toes and died of respiratory insufficiency as a neonate. The parents of the 2 sibships were related; the mothers were sisters and the fathers were brothers. Stuve and Wiedemann (1971) postulated that the disorder in this family represented a specific condition.
Farrell et al. (1987) described a newborn male with severe manifestations resulting in death at 12 days of age.
Kozlowski and Tenconi (1996) reported a 3-year-old boy with Stuve-Wiedemann syndrome. At age 30 months, he had short limbs with an increased upper to lower segment ratio, bowing of the femora, tibiae, and radii, with decreased extension at the knees and elbows. He had short fingers with flexion of all the small joints in the hand and adduction of the thumb, as well as camptodactyly of the second through fourth fingers. Talipes valgus was observed. On radiographic examination, bowing of the long bones of the lower limbs and forearms was documented; wide metaphyses with decreased density and abnormal trabecular pattern were also seen. Kozlowski and Tenconi (1996) discussed the differential diagnosis of Stuve-Wiedemann syndrome, campomelic dysplasia (114290), and kyphomelic dysplasia (211350).
Al-Gazali (1993) and Al-Gazali et al. (1996) reported 11 children in 5 families from the United Arab Emirates with what they termed 'severe neonatal Schwartz-Jampel syndrome type 2.' All presented at birth with skeletal abnormalities and feeding difficulties. Five had the typical pursed appearance of the mouth. Nine died from respiratory complications: 5 in the neonatal period and 4 before 2 years of age. The patients were mostly of Omani origin. Only 7 of 17 previously reported neonatal SJS cases had a similar severe course, suggesting to Al-Gazali et al. (1996) that there is a subgroup of SJS with severe respiratory and feeding problems, poor prognosis, and early death.
Chabrol et al. (1997) reported 3 newborn boys from 2 consanguineous Gypsy families with manifestations of Stuve-Wiedemann syndrome. The 2 families were presumably unrelated. Two of the infants died shortly after birth, whereas the third was alive at the age of 1 year. Besides hyperthermic episodes, 1 patient had hyperaminoaciduria, hepatic failure, and megaloblastic anemia, which prompted investigation of the mitochondrial respiratory chain in 2 cases. Abnormal results consisting of decreased activities of complexes I and IV were found in both patients. The finding of the Stuve-Wiedemann phenotype and abnormal mitochondrial metabolism from each of 2 infants from different families supported a pathogenetic relationship between the 2. Radiographs of the bony angulations were displayed.
Giedion et al. (1997) reported 2 sibs with neonatal SJS. One of them showed short, bowed femora and fetal hypokinesia on ultrasound at 17 weeks' gestation. Both were severely affected with mask-like facies, myopia, and multiple skeletal anomalies. One died at age 3 months, whereas the other was alive at age 9 years with normal intelligence, but was severely physically handicapped. Linkage was excluded from the SJS1 locus on chromosome 1p.
Cormier-Daire et al. (1998) reported findings in 8 patients with STWS suggesting that the syndrome is clinically homogeneous. All patients had feeding and swallowing difficulties, respiratory insufficiency, abnormal appearance, muscle hypotonia, and postnatal short stature. Recurrent episodes of unexplained fever occurred in all and were the cause of death in 6 of the 8 patients. Parental consanguinity and sib recurrence suggested autosomal recessive inheritance.
Cormier-Daire et al. (1998) suggested that STWS and neonatal Schwartz-Jampel syndrome, or SJS type 2, were the same entity based on similar clinical, radiologic, and histologic features. Superti-Furga et al. (1998) also concluded that Schwartz-Jampel syndrome type 2 and Stuve-Wiedemann syndrome should be considered the same entity. To test for possible nosologic identity between these disorders, they reviewed the literature and obtained a follow-up of the only 2 surviving patients, one with SJS type 2 at age 10 years and another with STWS at age 7 years. Patients reported as having either neonatal SJS or STWS presented a combination of a severe, prenatal-onset neuromuscular disorder with congenital joint contractures, respiratory and feeding difficulties, tendency to hyperthermia, and frequent death in infancy and a distinct campomelic-metaphyseal skeletal dysplasia. The follow-up observation of an identical and unique pattern of progressive bone dysplasia in the 2 patients (one with SJS type 2, one with STWS) surviving beyond infancy added to the evidence in favor of identity.
Raas-Rothschild et al. (2003) reported 2 sibs with Stuve-Wiedemann syndrome who died of respiratory failure due to pulmonary hypertension. The parents were first-cousin Muslim Arabs originating from the Jerusalem area. Echocardiographic and postmortem analysis showed that both patients had a closed ductus arteriosus, dilated pulmonary arteries with extremely hypertrophied walls, and right-to-left shunting through a patent foramen ovale. The authors postulated a mechanism in which antenatal premature closure of the ductus arteriosus could result in increased right ventricular afterload and increased pulmonary artery pressure, ultimately causing pulmonary artery hypertrophy and hypertension. Raas-Rothschild et al. (2003) suggested that some patients with Stuve-Wiedemann syndrome and early neonatal death due to respiratory failure may have had pulmonary hypertension.
Patients with Longer Survival
Stuve-Wiedemann syndrome is typically lethal in the neonatal period. Chen et al. (2001), who described the case of a child surviving to age 9 years, stated that only 2 patients with long survival had been reported. In addition to characteristic features of STWS, their patient had a number of unique clinical signs, including lack of corneal and patellar reflexes, smooth tongue with no fungiform papillae, chronic gingival abscesses, mottled and otherwise poor dentition, blotchy pigmentation of the skin, unusual infections, multiple fractures, and progressive scoliosis. Cytogenetic analysis identified mosaicism for a supernumerary marker chromosome, seen in the majority of amniocytes, blood cells, and skin fibroblasts. The marker chromosome was shown to be derived from chromosome 5 and to contain euchromatin.
Al-Gazali et al. (2003) reported 3 children from 2 inbred Arab families with Stuve-Wiedemann syndrome who had survived the first year of life; their ages were 6, 2.8, and 2 years. All exhibited a characteristic phenotype resembling that described by Chen et al. (2001). In all 3 children, the skeletal abnormalities progressed to severe bowing of the long bones with prominent joints and severe spinal deformity. All exhibited neurologic symptoms including temperature instability with excessive sweating, reduced pain sensation with repeated injury to the tongue and limbs, absent corneal reflexes, and a smooth tongue. All 3 children had normal intelligence. Radiologic changes included undertubulation of the diaphyses, rarefaction and striation of metaphyses, destruction of the femoral heads, and spinal deformity. This report confirmed that survival in this syndrome is possible and that the prognosis improves after the first year of life. It also supported the existence of a characteristic phenotype in Stuve-Wiedemann syndrome survivors that includes neurologic symptoms reminiscent of dysautonomia in addition to the skeletal abnormalities and distinctive radiologic features.
Gaspar et al. (2008) reported long-term follow-up of a 12-year-old girl, born of consanguineous Portuguese Gypsy parents, with STWS confirmed by genetic analysis (151443.0004). Early in infancy she had hypotonia, facial myotonia, low-set ears, a short neck, short bowed limbs, contractures of the elbows and knees, camptodactyly, and talipes equinovarus. She was a poor feeder and had recurrent bouts of fever and recurrent respiratory problems. In the ensuing years, she developed severe corneal opacities, progressive scoliosis, more prominent joint contractures, and ulnar deviation of the hands. Autonomic instability included poor body temperature regulation, with asymmetric and paradoxical sweating, and areas of hypoperfusion and hyperperfusion of the trunk and extremities. Her cognitive development was excellent. Other features included absent corneal reflexes, smooth tongue, and poor dentition with chronic dental abscesses. She lost her ability to walk and became wheelchair dependent at age 9. In a review of the few STWS patients with long survival, Gaspar et al. (2008) concluded that the major symptoms influencing daily life in these patients are loss of vision, paradoxical sweating/shivering, severe spinal deformity, spontaneous fractures, and limited mobility.
Yesil et al. (2014) reported 6 children from 4 unrelated families with Stuve-Wiedemann syndrome. Three of the patients died in infancy, and the 3 surviving patients were 2, 4.5, and 6 years old at the time of the report. All patients had prolonged and severe respiratory, feeding, and swallowing problems as well as episodic hyperthermia, recurrent infections, and dysmorphic facial features. The older children had severe osteoporosis, poor growth, and skeletal and joint abnormalities. Unusual features included inflammatory lesions on the distal extremities, oral ulcers, and tongue biting.
Melone et al. (2014) reported a 33-year-old woman with a protracted course of Stuve-Wiedemann syndrome. She had severe feeding difficulties from birth, resulting in growth and developmental delay. She also had respiratory distress in early childhood and recurrent fevers. She was noted to sweat very little in hot weather, but to sweat profusely on the face, arms, and upper trunk when exposed to cold temperatures or when stressed. Later in childhood she developed progressive scoliosis with secondary spastic paraparesis. Dysmorphic features included narrow face, high-arched palate, and low-set ears. Additional skeletal anomalies included short stature, cubitus valgus, contractures at the elbows, small hands with clinodactyly, deformed left foot, and misshapen toes; however, she did not have dysplasia of the long bones. As a young adult, she had a mild axonal sensorimotor neuropathy and paradoxical sweating, but remained ambulatory and had normal cognition. Skin biopsy showed an unusual pattern of autonomic and somatic cutaneous innervation consistent with abnormal postnatal cholinergic differentiation of sympathetic neurons innervating sweat glands. She was pregnant at the time of report.
InheritanceWiedemann and Stuve (1996) gave an update and a historical footnote, and noted that reported cases were consistent with autosomal recessive inheritance.
MappingGiedion et al. (1997) and Brown et al. (1997) demonstrated that neonatal Schwartz-Jampel syndrome type 2 was not linked to chromosome 1p36.1-p34, where 'classic' Schwartz-Jampel syndrome maps.
Through a study of a series of 19 patients with STWS/SJS2, Dagoneau et al. (2004) mapped the disease gene to chromosome 5p13.1 at marker D5S418.
Molecular GeneticsIn patients with Stuve-Wiedemann syndrome, Dagoneau et al. (2004) identified mutations in the leukemia inhibitory factor receptor gene (LIFR; see, e.g., 151443.0001-151443.0003). Some of the patients had been reported earlier by Al-Gazali et al. (1996, 2003), Chabrol et al. (1997), Cormier-Daire et al. (1998), and Superti-Furga et al. (1998).
In 6 patients from 4 unrelated Turkish families with Stuve-Wiedemann syndrome, Yesil et al. (2014) identified a homozygous truncating mutation in the LIFR gene (R692X; 151443.0006). Haplotype analysis suggested a founder effect.
In a 33-year-old woman with a protracted course of Stuve-Wiedemann syndrome, Melone et al. (2014) identified a homozygous missense mutation in the LIFR gene (P724A; 151443.0006). Genomewide SNP arrays, including parental samples, revealed a complete maternal isodisomy for chromosome 5; the mother carried the mutation in heterozygosity and no trace of paternal chromosome 5 was found from patient blood or skin biopsies. Transfection studies in Hep3B cells showed that the mutation caused abnormal receptor glycosylation and that the mutant receptor had decreased downstream activity compared to wildtype.
NomenclatureChabrol et al. (1997) used the abbreviation SWS for this disorder, but this abbreviation had already been used for Sturge-Weber syndrome (185300).