Genetic disorders

Infant and Mother With White Forelocks

KEELY M. FITZGERALD, DO and ANAND GOURISHANKAR, MD

Dr Fitzgerald is an intern in the pediatric neurology program and Dr Gourishankar is assistant professor of community and general pediatrics at Children’s Memorial Hermann Hospital and University of Texas Health Science Center at Houston.

Golder N. Wilson, MD, PhD––Series Editor: Dr Wilson is clinical professor of pediatrics at Texas Tech University Health Sciences Center in Amarillo, Lubbock, and El Paso. He is also on the staff at KinderGenome Pediatric Genetics in Dallas.

waardenburg syndrome

History

A 2-day-old term Hispanic/Caucasian infant in the well-baby nursery was noted to have a white forelock. Labor and delivery had been unremarkable and remaining physical examination findings were normal.

The patient’s mother had a white forelock as well. She also had other morphological alterations, including widely placed inner canthi and large hypopigmented macules on her abdomen.

•WHAT DIAGNOSIS WOULD YOU SUSPECT?

•IS THE WHITE FORELOCK A BENIGN OR CONCERNING FINDING?

(Answers and discussion on next page.)

waardenburg syndrome

(Photo courtesy of Amand Gourishankar, MD.)

ANSWERS:

The infant had a strong family history of Waardenburg syndrome (WS) that included an affected mother and the infant’s sibling as well as a maternal aunt, grandmother, and great grandfather.

WS is a rare dominant disorder with incomplete penetrance and variable expressivity that alters neural crest development. The syndrome was first described by the Dutch Ophthalmologist, P. J. Waardenburg, who noted the appearance of 6 distinctive features involving anatomical and pigmentary anomalies of the eye, skin, and hair as well as deafness across family members.1

CLINICAL MANIFESTATIONS

WS has been classified into 4 subtypes based on an array of clinical features. Diagnosis is made by the presence of 2 major or 1 major and 2 minor features.2

Major clinical features include:

•Sensorineural hearing loss.

•Pigmentary disturbances of iris.

•Complete, partial, or segmental heterochromia or hypoplastic blue eyes.

•Hair hypopigmentation, white forelock (poliosis), which occurs in many animal species as well as in humans.

•Dystopia canthorum (lateral displacement of the inner canthi).

•Affected first-degree relative.

Minor clinical features include:

•Congenital leucoderma: several areas of hypopigmented skin.

•Synophrys or medial eyebrow flare.

•Broad and high nasal root.

•Hypoplasia of alae nasi.

•Premature graying of hair.

PREVALENCE AND ETIOLOGY

WS affects an estimated 1 in 10,000 to 20,000 persons and accounts for 3% of congenital sensorineural deafness.3 Both sexes are affected equally.

Six genes are known to be involved in the syndrome: PAX3 (encoding paired box 3 transcription factor), MITF (microphthalmia-associated transcription factor), EDN3 (endothelin 3), EDNRB (endothelin receptor type B), SOX10 (encoding the Sry bOX10 transcription factor), and SNAI2 (snail homolog 2).4

WS type 1 and WS type 3 (Klein-Waardenburg syndrome) are caused by point mutations in PAX3 (chromosomal locus 2q35) and are autosomal dominantly inherited. WS type 1 is characteristic for the presence of dystopia canthorum (in 99% of patients) and less commonly for hearing loss (about 25% of patients).5,6 There is also an association with spina bifida. Cases of WS type 3 may appear sporadically in families with WS type 1 and the presence of musculoskeletal anomalies ranging from minimal contractures of fingers to hypoplasia of upper limbs or pectoral girdle.

WS type 2 is autosomal dominant and genetically heterogenous disorder, with 15% of cases having mutations in MITF.3,5 Clinically, it is more variable in presentation, with frequent absence of dystopia canthorum and higher incidence of sensorineural hearing loss.

The autosomal recessive WS type 4 is associated with Hirschsprung disease (Waardenburg-Shah syndrome). Mutations in SOX10, EDN3, or EDNRB are often present in WS type 4, but it is also genetically heterogeneous.

DIAGNOSIS AND PROGNOSIS IN THIS CASE

Diagnosis of WS type 1 in our patient was made on the basis of the clinical features and strong family history. The mother reported that no members of her family had associated deafness, and the child’s newborn hearing screening was normal. We expect that the condition in this patient will remain benign. n