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Progressive neurological deterioration in a child with distal arthrogryposis and whistling face
  1. DORIT LEV*,
  1. * Department of Medical Genetics, Wolfson Medical Centre, Holon, Israel 58100
  2. Paediatric Neurogenetic-Metabolic Clinic, Wolfson Medical Centre, Holon, Israel 58100
  3. Paediatric Orthopaedic Department, Dana Children's Hospital, Tel-Aviv Medical Centre, Tel-Aviv, Israel

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    Editor—Freeman-Sheldon syndrome (FSS) (McKusick 193700), described in 1938, is characterised by a whistling face with a long philtrum, a puckered mouth, microstomia, H shaped cutaneous dimpling on the chin, multiple joint contractures with camptodactyly, ulnar deviation of the fingers, bilateral talipes equinovarus, and kyphoscoliosis.1 Burian rediscovered the entity and called it the “whistling face syndrome”.2 There is genetic heterogeneity.3-6 Both autosomal dominant7 8 and recessive inheritance9-12have been described.

    The psychomotor development of affected children is usually normal in the autosomal dominant forms,6 13 14 although mild motor delay attributable to joint anomalies has been reported occasionally.3 15-18 A few patients with severe developmental retardation have been described, all with autosomal recessive inheritance.19-22

    We describe a child who presented from birth with distal arthrogryposis, profound mental retardation, severe hypotonia, and whistling face. The severe neurological involvement precludes him from having FSS according to the classification of Bamshadet al.23 We suggest that patients with a whistling face, distal contractures, and severe neurological involvement should be diagnosed as having a separate autosomal recessive syndrome.

    The patient was the first child of non-consanguineous, healthy, Moroccan Jews. The pregnancy was attained by in vitro fertilisation and was unremarkable. He was born at 42 weeks' gestation. Apgar scores were 4 at one minute and 6 at five minutes; pH was 7.11 and improved with bicarbonate infusion. A single seizure on the second day did not recur following phenobarbital therapy. Hypotonia with scarce spontaneous movements but increased reflexes was first noticed then. Length, weight, and head circumferences were on the 50th centile.

    He was first evaluated at the age of 6 months when his weight had dropped below the 5th centile. Physical examination showed a puckered mouth, mild retrognathia, camptodactyly of fingers 2 and 3, adducted thumbs, and rocker bottom feet (fig 1). Brain CT and MRI scans, EEG, echocardiogram, karyotype, and muscle biopsy including electron microscopy were normal. A diagnosis of the fetal hypokinesia sequence was considered at that time. A metabolic evaluation, including blood lactic, pyruvic, amino, phytanic, and very long chain fatty acids and urinary organic and bile acids, was normal.

    Figure 1

    The patient in the neonatal period with puckered mouth and H shaped cutaneous dimpling of the chin.

    At the age of 36 months clinical examination showed whistling face, micrognathia, a small mouth with a long philtrum and downturned upper lip, blepharophimosis, prominent and narrow forehead, and bitemporal balding. Height was on the 20th centile, head circumference was on the 2nd centile, and weight was on the 50th centile for 12 months (−3 SD for his age). He was very thin, with an expressionless face and bilateral hand contractures with camptodactyly and ulnar deviation. His chest was flat with decreased anterior-posterior diameter (fig 2). Limb movements were scarce and there was no head control. He was able to follow with his eyes but could not smile. Eye examination was normal. Bronchoscopy showed severe laryngomalacia. There were frequent desaturations with CO2 retention. The muscles were atrophic but reflexes were increased. There has been no neurological development since birth.

    Figure 2

    The patient at the age of 3 years. Note the whistling face, long philtrum, blepharophimosis, narrow forehead, extreme failure to thrive, flat chest, camptodactyly, and adducted thumbs.

    A repeat brain MRI showed generalised cerebral, cerebellar, and brain stem atrophy (fig 3). Further evaluation including isoelectric focusing of transferrins and spectral karyotyping of his chromosomes was normal.

    Figure 3

    MRI at the age of 3 years. T1 weighted coronal image. Prominent cerebral and cerebellar atrophy.

    Freeman-Sheldon syndrome (FSS) was classified among the congenital arthrogryposis syndromes assuming a possible myopathic origin of both facial anomalies and joint contractures.14 However, EMG and structural abnormalities have not always been detected in the muscles involved.14 24-26 In addition, the most frequently described muscle abnormality, substitution of muscle tissue with connective tissue, may be a consequence rather than a cause of joint immobility.3

    Congenital arthrogryposis is part of the fetal akinesia sequence. There are multiple pathogenic factors involved in fetal hypokinesia, such as central nervous system malformations, spinal cord disease, neuromuscular disorders, and a restricted fetal environment.20 There are also numerous syndromes that present with this sequence. In the Marden-Walker and Pena-Shokeir syndromes the cause of the akinesia is unclear. Bamshadet al 23 recently included FSS as one of the distal arthrogryposes and designated it DA2. Their definition of a distal arthrogryposis is “an inherited primary limb malformation disorder characterised by congenital contractures of two or more different body areas and without primary neurologic and/or muscle disease that affects limb function”. Indeed in most of the reported cases intelligence was described as normal; this includes all cases with autosomal dominant inheritance6 13 14 and some of the cases with autosomal recessive inheritance.12

    Recently, a variant of FSS with dominant inheritance has been mapped to chromosome 11p15.5-pter.4 A small group of patients with severe central nervous system involvement and presumed autosomal recessive inheritance has been described (table 1).

    Table 1

    Comparison of the present patient to those previously reported

    Illum et al 19 reported two sisters and a brother from a sibship of four who were born with multiple joint contractures, camptodactyly, an expressionless face with a puckered mouth, and restricted mouth opening. There were widespread calcium deposits in the leptomeninges, on the surface of the cerebral convolutions, and throughout the brain. Calcification was also found in skeletal muscles.9 Schrander-Stumpelet al,20 Di Roccoet al,21 Zampinoet al,22 and Hagemanet al 27 reported other similar cases. Schrander-Stumpel et al 20 reported three unrelated patients who had distal arthrogryposis, severe developmental retardation, and a “whistling face” associated with the Pierre-Robin sequence. Zampinoet al 22 described a sporadic case of the whistling face syndrome in a boy who also had severe hypertonia, swallowing problems, poor weight gain, and cerebellar and brain stem atrophy. They suggested that primary brain anomalies may explain many of the syndrome's manifestations. They suggested it might be more appropriate to speak of the Freeman-Sheldon spectrum rather than syndrome because of the different pathogenic mechanisms (muscular, skeletal, and neurological), the wide range of clinical manifestations, and the genetic heterogeneity.

    Our patient manifests characteristic features of whistling face with profound mental retardation and central hypotonia (normal muscle biopsy). An MRI obtained at the age of 6 months was normal, but a repeat study at the age of 3 years showed progressive cerebral, cerebellar, and brain stem atrophy (fig 3). Schrander-Stumpelet al 20 described a slightly enlarged cisterna magna and interhemispheric fissure in one patient and ventricular enlargement in the other, and Zampinoet al 22 found atrophy of the brain stem and the cerebellum, both on CT scans.

    We suggest that there may be several distinct genetic syndromes with whistling face and distal contractures, one autosomal dominant with no neurological involvement, fitting the definition of the distal arthrogryposes and designated DA2, and the others possibly autosomal recessive with variable central nervous system involvement. The syndromes with normal intelligence may be caused by a primary abnormality of tendon growth and development,23 while the others may be attributed to a primary or secondary brain anomaly as suggested by several authors.19-22 The progressive atrophy seen on our patient's MRI may suggest that features of whistling face with severe neurological involvement may not be the result of a primary brain malformation but rather an as yet unknown metabolic neurodegenerative disorder, starting in utero and causing fetal hypokinesia and prominent hypotonia from birth. The lack of any developmental milestones, the acquired microcephaly, failure to thrive, and early death are manifestations of the postnatal downhill course in this disorder. The early death seen in most of the patients (table 1) may be attributed to brain stem involvement with progressive feeding and respiratory difficulties. Our patient underwent an extensive metabolic evaluation. We have ruled out organic and amino acidurias, peroxisomal and mitochondrial disorders, and recently also disorders of glycoconjugates, which have been implicated in patients with developmental delay and cerebellar atrophy.28 Deficiency of a factor important in both pre- and postnatal brain development may be the primary abnormality in this syndrome. More cases are needed to understand and delineate this syndrome further and to facilitate mapping.