Bosma Arhinia Microphthalmia Syndrome

A number sign (#) is used with this entry because of evidence that Bosma arhinia microphthalmia syndrome (BAMS) is caused by heterozygous mutation in the SMCHD1 gene (614982) on chromosome 18p11.

Description

Bosma arhinia microphthalmia syndrome (BAMS) is characterized by severe hypoplasia of the nose and eyes, palatal abnormalities, deficient taste and smell, inguinal hernias, hypogonadotropic hypogonadism with cryptorchidism, and normal intelligence (summary by Graham and Lee, 2006).

Also see absence of nasal bones (161480).

Clinical Features

Gifford et al. (1972) reported 2 unrelated male patients with congenital absence of the nose and anterior nasopharynx. Bosma et al. (1981) restudied these patients and noted that they also had hypoplasia of the eyes, sensory abnormalities of taste and smell, impaired vision with cataracts and colobomata, bilateral inguinal hernias, cryptorchidism, and hypogonadotropic hypogonadism. Although the cranial vaults, orbits, epipharynges, and oral cavities were indented toward the hypoplastic nasal composite, the peripheral dimensions of their faces were normal for age and they had normal intelligence.

Ruprecht and Majewski (1978) reported arhinia, choanal atresia, microphthalmia, and cleft palate in 2 daughters of healthy parents.

Thiele et al. (1996) reported a 3-generation German family in which a 5-year-old girl with complete absence of the nose and nostrils had hypertelorism, microphthalmia of the left eye and right-sided clinical anophthalmia, high palate, choanal atresia, preauricular pits, and bilateral absence of the twelfth ribs. She had normal motor and mental development. A similarly affected maternal aunt had died 2 hours after birth. The proband's mother and maternal grandmother both exhibited only a broad nasal tip and asymmetric nostrils, as well as high palate in the mother and diastema between the upper central incisors in the grandmother. Thiele et al. (1996) noted similarities between the proband and the patients described by Ruprecht and Majewski (1978), and considered the condition to be dominantly inherited with reduced penetrance.

Olsen et al. (2001) reported a female Norwegian infant who was born with absence of the external nose, high-arched palate, slight hypertelorism, and bilateral colobomata of the iris. Routine prenatal ultrasound examination had shown diffuse midface anomalies with edema at 17 weeks' gestation, and absence of the external nose was diagnosed prenatally at 25 weeks' gestation. Facial CT during the neonatal period showed absence of nasal bones, cribriform plate, and septal structures, including the vomer, perpendicular plate of the ethmoid bone, and septal cartilage. The maxillae were hypoplastic with a high-arched bony palate. Cranial MRI confirmed the CT findings, and also showed absence of the olfactory bulbs. Olsen et al. (2001) reviewed 22 previously reported cases of congenital absence of the nose, noting the frequent association with ocular anomalies, including hypertelorism, unilateral or bilateral microphthalmia, coloboma of the iris, and occluded or absent nasolacrimal ducts. Associated central nervous system anomalies included frontal encephalocele and absence of olfactory tracts.

Graham and Lee (2006) described 2 unrelated males with congenital arhinia, choanal atresia, microphthalmia, cryptorchidism, hypogonadotropic hypogonadism, and normal or near-normal intelligence.

Tryggestad et al. (2013) reported a 13-year-old boy with arhinia, midface hypoplasia, anosmia, and hypogonadotropic hypogonadism. CT imaging revealed lack of nasal bones, absence of sinus cavities and lacrimal glands, and maxillary hypoplasia. The patient presented at age 13 years for evaluation of delayed puberty and micropenis; gonadotropin and testosterone levels were consistent with severe hypogonadotropic hypogonadism. Tryggestad et al. (2013) did not consider this patient to have Bosma syndrome because he did not have microphthalmia.

Becerra-Solano et al. (2016) reported a 19-month-old Mexican boy with arhinia, bilateral clinical anophthalmia, choanal atresia, and high palate, as well as small penis, undescended testes, and hypoplastic scrotum. The authors stated that this was the fifteenth reported case of BAMS, and the first reported Mexican case.

Brasseur et al. (2016) studied a man in his forties who was born with arhinia, choanal atresia, bilateral microphthalmia with coloboma, and hypogonadotropic hypogonadism. He experienced osteoporotic fractures after a fall from standing height at age 35 years, and bone density was found to be below expected values, which the authors suggested was likely secondary to hypogonadotropic hypogonadism. Echocardiography showed effacement of the sinotubular ridge at the aortic root. The patient had normal cognitive function. The proband's father had been diagnosed with limb-girdle muscular dystrophy, but had no vision abnormalities, anosmia, or other features of Bosma syndrome. The paternal grandmother had coloboma and cataract, and a paternal great-aunt reportedly had coloboma and a paternal great-uncle was reportedly born blind.

Brasseur et al. (2016) tabulated the clinical findings from 14 reported BAMS patients and suggested that the criteria for BAMS should include arhinia, midface hypoplasia (hypoplastic maxilla), and normal cognition, as well as hypogonadotropic hypogonadism in males. Microphthalmia with or without coloboma, high-arched palate, anosmia, absent paranasal sinuses, and absent olfactory bulbs would also be important findings.

In a series of 14 probands with arhinia, Gordon et al. (2017) observed pubertal delay or anomalies of menarche in all 3 postpubertal female patients. They suggested that reproductive axis defects associated with arhinia are likely secondary to a defect in GnRH neuron production in, or migration from, the olfactory placode.

Shaw et al. (2017) summarized the clinical findings in 40 patients from 38 families with arhinia, including patients previously reported by Gifford et al. (1972), Ruprecht and Majewski (1978), Bosma et al. (1981), Muhlbauer et al. (1993), Thiele et al. (1996), Olsen et al. (2001), Graham and Lee (2006), Tryggestad et al. (2013), Becerra-Solano et al. (2016), and Brasseur et al. (2016); 6 of the patients were also studied by Gordon et al. (2017). All affected individuals had complete arhinia, accompanied in most cases by other craniofacial abnormalities, including high-arched or cleft palate, absent paranasal sinuses, hypoplastic maxilla, nasolacrimal duct stenosis or atresia, and choanal atresia. Ocular phenotypes included anophthalmia or microphthalmia (77%), uveal coloboma (79%) and cataract (53%), and 6 patients had normal eye anatomy and vision. Dysmorphic pinnae or low-set ears were seen in 41%. Of 31 assessable subjects (22 male and 9 female), 97% demonstrated hypogonadotropic hypogonadism (HH), and the 7 subjects for whom brain MRI data were available had no olfactory structures.

Molecular Genetics

By whole-genome, whole-exome, and targeted sequencing in 38 probands with arhinia, Shaw et al. (2017) identified heterozygous missense mutations in the SMCHD1 gene in 32 (84%) of the probands, including patients previously reported by Gifford et al. (1972), Ruprecht and Majewski (1978), Bosma et al. (1981), Muhlbauer et al. (1993), Thiele et al. (1996), Olsen et al. (2001), Graham and Lee (2006), Tryggestad et al. (2013), Becerra-Solano et al. (2016), and Brasseur et al. (2016) (see, e.g., 614982.0007-614982.0015). The mutations all occurred within exons 3 to 13, spanning a GHKL-type ATPase domain. Functional analysis indicated that the mutations were likely loss-of-function variants. Noting the marked intra- and interfamilial phenotypic variability in the SMCHD1-mutated families, Shaw et al. (2017) suggested that SMCHD1 variants are not fully penetrant and that such variants alone may not be sufficient to cause arhinia.

Simultaneously and independently, Gordon et al. (2017) performed whole-exome sequencing and/or Sanger sequencing in 14 probands with arhinia, 6 of whom were also studied by Shaw et al. (2017). They identified mutations in the SMCHD1 gene in all 14 probands (see, e.g., 614982.0008, 614982.0013, and 614982.0014), including a Japanese boy previously reported as patient B by Sato et al. (2007) and an Irish girl described by Courtney et al. (2014). The mutations were shown to have occurred de novo in the 11 families for which DNA was available from the parents; all occurred at highly conserved residues within the ATPase domain and none was found in public variant databases. In contrast to the findings of Shaw et al. (2017), functional analysis by Gordon et al. (2017) was consistent with gain-of-function or neomorphic activity by the BAMS-associated missense variants.

Exclusion Studies

In a sporadic female patient with arhinia, bilateral microphthalmia, and iris coloboma, in whom Hou (2004) had detected a de novo chromosomal translocation, t(3;12)(q13.2;p11.2), Sato et al. (2007) performed BAC-based FISH and whole-genome array CGH and identified an approximately 19-Mb deletion spanning 3q11.2 to 3q13.21, but found no disruption of any genes at the 12p11 breakpoint. Array CGH in 4 additional arhinia patients, including a German girl previously studied by Muhlbauer et al. (1993) and the Norwegian girl originally reported by Olsen et al. (2001), showed no copy number aberrations, and direct sequencing of 2 candidate genes within the deleted region showed no mutations.

In a 13-year-old boy with arhinia, anosmia, and hypogonadotropic hypogonadism, Tryggestad et al. (2013) analyzed 7 Kallmann syndrome (see 308700)-associated genes, but no mutations were detected. Array CGH showed no chromosome imbalances.

In a 19-month-old Mexican boy with BAMS, Becerra-Solano et al. (2016) sequenced the candidate gene PAX6 (607108) but did not find any mutations.

In a man with BAMS, Brasseur et al. (2016) sequenced 8 candidate genes but did not find a causative mutation; array CGH showed no copy number variation, and whole-exome sequencing of the patient and his parents did not reveal a causative variant.