B-Cell Immunodeficiency, Distal Limb Anomalies, And Urogenital Malformations

Description

The BILU syndrome comprises humoral immunodeficiency, distal limb anomalies, dysmorphic facial features, and urogenital malformations inherited in an autosomal dominant pattern. The disorder referred to as Hoffman syndrome shows many similar features, suggesting that they represent the same disorder (summary by Hugle et al., 2011).

Clinical Features

Edery et al. (2001) described a 3-generation family in which 4 members had a combination of B-cell immunodeficiency, distal limb abnormalities, genitourinary malformations, and mild dysmorphic features. All 4 had normal intelligence and growth. Edery et al. (2001) proposed the acronym BILU for B-cell immunodeficiency, limb anomalies, and urogenital malformations. They pointed to hypospadias and symphalangism, each of which was present in 2 cases, as diagnostically useful features. One instance of male-to-male transmission and marked intrafamilial variable expression of the disorder suggested autosomal dominant inheritance.

Tischkowitz et al. (2004) reported an affected mother and daughter with features similar to those reported by Edery et al. (2001). The proband was a 31-year-old woman from Cyprus who was diagnosed with hypogammaglobulinemia due to B-cell deficiency in infancy. She had subtle dysmorphic features, including mild hypertelorism, prominent supraorbital ridges, prominent columella, and mild mandibular hypoplasia. Distal limb anomalies included small narrow hands with small thumbs and fifth finger clinodactyly, and small narrow feet with short, partially overlapping toes. Radiographs showed shortening of the first metacarpals and metatarsals. She was thought to have clitoromegaly at birth, which resolved with age. Her 5-month-old daughter developed recurrent infections and was found to have hypogammaglobulinemia. She also had clitoromegaly at birth and facial and distal limb features similar to those of her mother. Comparison with the family of Edery et al. (2001) suggested that the more severe urogenital abnormalities occurred predominantly in males.

Hoffman et al. (2001) reported a 6-year-old girl with isolated humoral immune deficiency, dysmorphic facial features, and mild distal limb anomalies. She had an unaffected dizygotic twin sister. The patient had onset of recurrent infections during the first year of life, and presented at age 6 for immune work-up. Laboratory studies showed absent B cells, markedly decreased levels of IgG and IgM, and deficient antibody response to vaccination. Lymphoid tissue showed no follicles, germinal centers, or plasma cells. T cells were normal. Dysmorphic features included microcephaly, bilateral epicanthal folds, sickle-shaped eyebrows, hypoplastic alae nasi, a thin upper lip, and marked micrognathia. She had an anteriorly placed anus, laterally displaced labia majora, hypoplastic labia minora, and redundant skin over the clitoris. Limb anomalies included hypoplastic thenar areas with absent thenar creases, abnormal creases on the second fingers compatible with a short middle phalanx, fifth finger clinodactyly, recessed great toes, and partial 4-5 syndactyly of the toes. Radiographs showed hypoplastic first metatarsals, severe varus anomalies, triphalangeal thumbs, and brachymesophalangy V. At age 2 years, she had a seizure with abnormal EEG, which later normalized. The report stated that she had slower development than her sister, but at age 10 years, she was performing acceptably in age-appropriate classes.

Hugle et al. (2011) reported a girl and her mother with a disorder similar to that reported by Hoffman et al. (2001). The proband was a 7.5-year-old girl who presented with recurrent infections. Laboratory studies showed severe hypogammaglobulinemia with an almost complete lack of B cells. T-cell studies showed some decrease in cytokine production with a normal mitogen response. Dysmorphic features included highly arched eyebrows, apparent hypertelorism, hypoplastic alae nasi, prominent columella, a small mouth with prominent incisors, micrognathia, and large, apparently low-set ears. The hands showed ulnar deviation of the index finger, fifth finger clinodactyly, and hypoplastic thumbs with decreased motility. Her feet showed metatarsus adductus. Genitalia were abnormal with clitoral hypertrophy and hypoplastic labia minora. Development was reportedly normal. Her mother had a similar, but milder immunologic phenotype, with no history of recurrent infections, but mild IgG1 deficiency and reduced numbers of B cells. However, her facial dysmorphism was significant, with hypoplasia of the lower lip combined with micrognathia necessitating several maxillofacial surgical procedures at an early age. Her hands were similar to those of her daughter.

Inheritance

The transmission pattern of the disorder in the families reported by Edery et al. (2001), Tischkowitz et al. (2004), and Hugle et al. (2011) was compatible with autosomal dominant inheritance.

Molecular Genetics

Exclusion Studies

Tischkowitz et al. (2004) screened for mutations in the HOXA13 gene (142959) in affected members of their family and the family reported by Edery et al. (2001) and found no mutations. They also found no evidence for microdeletion involving either HOXA13 or the HOXA (see 142950) cluster as a whole.