Laurin-Sandrow Syndrome

A number sign (#) is used with this entry because of evidence that Laurin-Sandrow syndrome (LSS) is caused by heterozygous mutation in an SHH (600725) regulatory element (ZRS) that resides in intron 5 of the LMBR1 gene (605522).

Clinical Features

Sandrow et al. (1970) described a father and daughter with ulnar and fibular dimelia and peculiar facies. At birth the father was noted to have hand and foot anomalies described as syndactyly and polydactyly. Operations to correct digital webs and remove several supernumerary toes were performed. Bilateral clefts enlarged the inferior posterior margins of the nares. The daughter had identical nasal clefts and mirror hands, with fusion of 10 digits in rosebud fashion bilaterally. The fibula and ulna were duplicated bilaterally and the radius and tibia were missing. Sandrow et al. (1970) considered that the case reported by Laurin et al. (1964) was 'almost identical' to their 2 cases. That was a boy who had complete polysyndactyly of his hands, which were held in a 'semicupped position,' and 'perfect mirror feet.' He also had bilateral absence of the radius and tibia with bilateral reduplication of the ulna and fibula.

Kogekar et al. (1993) described a single case and Martin et al. (1993) described an affected father and daughter. It is clear that abnormalities of the nose are particularly characteristic. Martin et al. (1993) pictured a deep groove in the columella of both father and daughter. The mirror-image hands had 'rosebud' appearance because of syndactyly. The mirror-image feet resulted in a fused midline hallux.

Martinez-Frias et al. (1994) described an isolated case. They pictured the particular nose with hypoplastic nasal alae and very sharp columella. They proposed that the disorder be called Laurin-Sandrow syndrome.

Hatchwell and Dennis (1996) reported a girl with mirror hands and feet and associated groove of the nasal columella. She was said to represent the sixth reported case of this combination of congenital anomalies. Mutation in a HOX gene was suggested by Hatchwell and Dennis (1996) as a likely candidate for the syndrome.

Matsumoto et al. (1997) found reports of 7 patients with mirror hands and feet. Parent-to-child transmission was reported in 2 families.

Kantaputra (2001) described a Thai man with Laurin-Sandrow syndrome, the ninth reported case. He had an underdeveloped nasal bone, scar-like seams under the nose, large heads of the mandibular condyles, and brachymesophalangy of toes as newly observed findings of the syndrome. He also had mental retardation. He showed duplication of the ulna with nonopposable triphalangeal thumbs and polydactyly of 1 finger. Mirror-image polydactyly of the toes was present. There were 9 toes on the right and 8 on the left. Synostosis of severely malformed tarsal bones was noted.

Kjaer et al. (2005) reported a father and son with nasal and limb defects characteristic of Laurin-Sandrow syndrome. Both individuals had distinct nasal defects, triphalangeal thumb, upper limb postaxial polydactyly, total syndactyly of all fingers, and lower limb preaxial mirror image polydactyly with tibia and fibula appearing alike. In the son, lower limb vessels were investigated by ultrasound and flow Doppler measurements. Bilaterally, 2 posterior tibial arteries were located medially and laterally, respectively, each ending in a separate plantar arcade supplying the toes with at least 1 vessel between every metatarsus. The anterior tibial artery was also duplicated and located in front of each of the 2 identical zeugopods ending in 2 sets of dorsal arcades. An additional and larger vessel was located between the 2 sets of duplicated vessels. These findings suggested that vessel formation in the lower limb is closely linked to the early patterning of the posteriorly located fibula and not tibia, which may seem surprising in the light of the anatomic nomenclature (e.g., of the anterior and posterior tibial artery).

Marino-Enriquez et al. (2008) reported a female infant, born at 33-weeks' gestation with multiple anomalies suggestive of LSS, who died at age 45 minutes. Postmortem examination showed abnormal face with prominent forehead, flat nose, hypertelorism, deep longitudinal groove in the columella, and inverse V-shaped mouth. There was polysyndactyly of the hands and feet with symmetric configuration and fusion of the nails. There were 7 metacarpals in each hand and foot. One foot had 12 toes, and the other had 11 toes, and both feet had an additional finger-shaped appendage on the internal aspect. Both tibiae were shorter than the fibulae; the forearm bones showed no abnormalities. Brain anomalies included absence of the olfactory sulci, ventricular dilatation, ectopic neurons, and diffuse gliosis. In a review of reports of the disorder, Marino-Enriquez et al. (2008) noted marked heterogeneity in the terminology and classification of polydactyly. The authors proposed that the entity LSS only be used in cases with symmetric tetramelic polysyndactyly, especially 'cup-shaped' hands and mirror feet, in association with nasal anomalies.

Segmental Laurin-Sandrow Syndrome

Innis and Hedera (2004) reported 2 unrelated boys with isolated left mirror hand and ulnar duplication. One patient had preaxial polydactyly of the left hand and limited flexion and extension of the left elbow and wrist. The left hand had 8 fingers and no thumb. Radiographic analysis showed absence of the radius and ulnar duplication; the left shoulder and upper arm were normal. The second child had a flexed wrist with 7 digits on the left hand and no thumb. Radiographic analysis of the left upper limb showed 2 ulnae and 7 triphalangeal digits. His father had a unilateral clubfoot and his mother had a mild hallux valgus. Neither child had nasal abnormalities. Innis and Hedera (2004) suggested that these patients had 'segmental' Laurin-Sandrow syndrome due to somatic mutation involving the precursor cells of the left upper limb.

Inheritance

Martin et al. (1993) thought that autosomal dominant inheritance was likely in their family. Martinez-Frias et al. (1994) stated that their sporadic case was born to a 39-year-old father, supporting the assumption of autosomal dominant new mutation.

Father-to-son transmission of Laurin-Sandrow syndrome in the family reported by Kjaer et al. (2005) excluded X-linked inheritance.

Cytogenetics

Ohashi et al. (1995) and Kim et al. (1997) reported a Japanese boy with mirror-image polydactyly who had a de novo 46,XY,t(2;14)(p23.3;q13) karyotype. Although the patient had no other anomalies, such as nasal and long-bone abnormalities, they considered that the disorder was a variant of mirror hands and feet and hypothesized that a gene that may determine anterior-posterior pattern in early developing limbs had been disrupted by a translocation breakpoint.

Matsumoto et al. (1997) identified a YAC clone spanning a translocation breakpoint at 14q13. They confirmed that the breakpoint was located between 2 specific loci within a distance of 0.6 cM. In a later study, Matsumoto et al. (1997) constructed a 1.2-Mb high-resolution physical map with a contig composed of 16 bacterial artificial chromosomes (BACs) and 6 P1-derived artificial chromosomes (PACs) at a region around the breakpoint, extending from the loci D14S75 to D14S728.

In the Japanese boy with postaxial mirror-image polydactyly and a de novo balanced chromosomal translocation, t(2;14)(p23.3;q13), who was originally reported by Ohashi et al. (1995) and Kim et al. (1997) and studied by Matsumoto et al. (1997), Kondoh et al. (2002) identified a novel gene, MIPOL1 (606850), that was disrupted at the 14q13 breakpoint. Two other unrelated patients with limb anomalies similar to mirror-image polydactyly failed to show mutations in the MIPOL1 gene. At the other breakpoint, 2p23.3, only the neuroblastoma-amplified protein gene (NAG) was identified, and it is located at least 50 kb centromeric to the breakpoint, making it unlikely to be causative for mirror-image polydactyly.

Molecular Genetics

In affected individuals from 3 families with Laurin-Sandrow syndrome, Lohan et al. (2014) screened for copy number variation in the 7q36 chromosomal region and detected heterozygosity for 3 different microduplications of the ZRS region in intron 5 of the LMBR1 gene (605522.0018-605522.0020), with duplication lengths varying from 16 to 75 kb. The array CGH results were confirmed by qPCR in the 3 index patients, and the microduplications segregated with disease in each family. Lohan et al. (2014) noted that compared with previously reported ZRS microduplication-associated syndromes, the family with the shortest duplication (16 kb; 605522.0008) had the most complex phenotype: the affected father and son, originally reported by Kjaer et al. (2005), exhibited bilateral complete syndactyly of the hands, aplasia of the patella and tibia, duplication of the fibula, and preaxial mirror-image polysyndactyly of the feet. In contrast, the family with the largest reported duplication (589 kb; 605522.0009) had triphalangeal thumb-polysyndactyly syndrome (see 174500).