Whistling Face Syndrome, Recessive Form

Description

Whistling face syndrome is characterized by an atypical facial appearance with anomalies of the hands and feet. Most cases show autosomal dominant inheritance: see distal arthrogryposis 2A (DA2A; 193700). There are rare reports of presumably autosomal recessive inheritance (summary by Altunhan et al., 2010).

Clinical Features

The whistling face syndrome was first described as craniocarpotarsal dystrophy by Freeman and Sheldon (1938). Burian (1963) rediscovered the entity and called it the 'whistling face syndrome.'

Zampino et al. (1996) described a sporadic case of the whistling face syndrome in a boy who also had severe hypertonicity, swallowing problems, and cerebellar and brainstem atrophy. The authors suggested that primary brain anomalies may explain many manifestations of the syndrome. They noted that it might be more appropriate to speak about the Freeman-Sheldon spectrum (193700) rather than syndrome because of the different pathogenetic mechanisms (muscular, skeletal, and neurologic), the wide range of clinical manifestations, and the genetic heterogeneity.

Altunhan et al. (2010) reported a 22-day-old boy, born of consanguineous Turkish parents, with whistling face syndrome. He was of small build with poor feeding, microcephaly, and decreased activity. His abnormal facial appearance included pinched lips, small mouth, microretrognathia, dimpling of the chin, prominent nasolabial folds, long philtrum, and a whistling-facial appearance particularly when crying. Both hands were contracted, with camptodactyly and ulnar deviation of the third and fourth fingers. Other features included bilateral inguinal hernias and cryptorchidism. He developed episodic high fever without evidence of infection or malignant hyperthermia that occurred every 2 to 3 days. During follow-up, he was reported to have gastrointestinal reflux and frequent lung infections.

Inheritance

Hashemi (1973) described a sporadic case with parental consanguinity; Alves and Azevedo (1977) reported affected sibs, offspring of normal consanguineous parents, suggesting autosomal recessive inheritance.

Kousseff et al. (1982) observed the syndrome in both of same-sex monochorionic, diamniotic twins who were shown by HLA typing to be dizygotic and whose parents were normal and unrelated. In the last pair of cases, the diagnosis was based on characteristic facies (prominent supraorbital ridges, sunken eyes, microstomia, puckered lips, H-shaped dimpling of chin) and hands (symmetric clenched fingers with camptodactyly and ulnar deviation).

Fitzsimmons et al. (1984) reported affected sibs, born of unaffected consanguineous parents, suggesting autosomal recessive inheritance.

Sanchez and Kaminker (1986) described affected brother and sister whose unrelated parents were unaffected. The authors considered that this most likely represented a recessive form of the disorder; other possibilities mentioned were germinal mosaicism for a dominant gene and an epistatic recessive gene that suppressed expression of the abnormal dominant gene in the father, whose parents were first cousins.

Wang and Lin (1987) described affected brothers born to normal, nonconsanguineous parents and suggested that this is evidence of autosomal or X-linked recessive inheritance.

Dallapiccola et al. (1989) described brother and sister with the whistling face syndrome who were born to unaffected parents. The features were typical of the autosomal dominant form. Parental germinal mosaicism was a distinct possibility.