Pallister-Hall syndrome (PHS), a pleiotropic autosomal dominant malformative disorder, is characterized by hypothalamic hamartoma, pituitary dysfunction, bifid epiglottis, polydactyly, and, more rarely, renal abnormalities and genitourinary malformations.
Approximately 100 patients have been reported to date.
Most patients with PHS present at birth with skeletal polydactyly of the third or fourth digit or postaxial polydactyly; either may be accompanied by cutaneous syndactyly and nail dysplasia. Facial features may include a short nose, flat nasal bridge, and low-set, posteriorly angled ears. Cleft palate, cleft uvula and multiple buccal frenula have been reported in some patients. An asymptomatic bifid epiglottis is nearly pathognomonic, however, some patients present with more severe posterior laryngeal clefts leading to potentially fatal respiratory insufficiency. Hypothalamic hamartoma is often asymptomatic, however, it may be associated with panhypopituitarism. Acute primary adrenal insufficiency (see this term) may also occur in severe cases, as well as milder forms of adrenal insufficiency. Precocious puberty manifests in some cases. Neurological involvement can include gelastic epilepsy (seizures that manifest as facial grimacing, smiling or laughter) or other seizure types. Renal agenesis or dysplasia as well as other genitourinary anomalies have been reported, including vaginal atresia or hydrometrocolpos, microphallus, or cryptorchidism. Other findings may include intrauterine growth retardation, abnormal lung lobation, generalized skeletal dysplasia with mesomelic shortening and radial bowing of limbs, imperforate anus and congenital heart defects.
PHS is due to mutations of the GLI3 gene (7p13) that encodes a transcription factor activated by the sonic hedgehog pathway. Mutations lead to alterations in gene expression during development.
Clinical diagnostic criteria of patients with at least one family member with PHS require two findings: hypothalamic hamartoma, visualized on magnetic resonance imaging (MRI) as a non-enhancing, midline hypothalamic mass that is isointense to gray matter on all pulse sequences, and central polydactyly. This may be confirmed by full sequence analysis of GLI3.
Differential diagnoses include oral-facial-digital syndrome type 6, Holzgreve-Wagner-Rehder syndrome, McKusick-Kaufman syndrome, Holt-Oram syndrome, Bardet-Biedl syndrome, Smith-Lemli-Opitz syndrome and congenital hypothalamic hamartoma syndrome as well as craniopharyngioma, Greig cephalopolysyndactyly syndrome and Ellis Van Creveld syndrome (see these terms).
Antenatal genetic testing may be considered in families harboring a known PHS causative mutation of GLI3 and fetal MRI can exclude hypothalamic hamartoma. However, familial occurrences of PHS are generally milder than sporadic ones.
PHS is autosomal dominant, passed on to 50% of offspring, but expression is highly variable and many cases are sporadic, due to de novo mutations.
Treatment is symptomatic. At birth, breathing of patients with polydactyly should be monitored and indirect laryngoscopy should be performed. Tracheotomy may be necessary. If present, surgical intervention for imperforate anus must be undertaken. Medical imaging should include MRI to assess the hypothalamic hamartoma, X-rays of hands and feet and a full-skeletal survey as well as renal ultrasound. Laboratory assessment including a full endocrinological and cholesterol synthesis analysis should be performed; multiple lifelong hormone replacement therapies may be required.
Prognosis should be assumed to be excellent until proven otherwise. However, in its most severe forms, panhypopituitarism and severe airway malformations can be lethal; imperforate anus may also be lethal if not recognized. Intellectual deficits and behavioral alterations have not been directly correlated with the syndrome.
Last update: May 2013