Ohdo syndrome in a Filipino teen

INTRODUCTION

Ohdo syndrome is a rare congenital disorder occurring in less than 1 in a million individuals, characterized by intellectual disability, craniofacial abnormalities, as well as appendicular abnormalities. Caused by pathogenic variants in the lysine acetyltransferase 6B gene (KAT6B), the orphan syndrome suffers from a paucity of reported cases, with less than 30 cases reported worldwide. Several clinical variants have been described, including the Say-Barber-Biesecker-Young-Simpson (SBBYS) variant. This subtype is associated with genital abnormalities in males, hypoplastic or absent patellae, joint contractures affecting the lower extremities, and developmental delay with varying degrees of intellectual disability. Additional findings may include hypotonia in infancy, feeding and respiratory difficulties, and digital anomalies such as elongated thumbs and halluces. Because of its rarity, individual case reports remain important in defining the phenotypic range and supporting clinical recognition. Here, we present detailed skeletal survey findings of a genetically confirmed case of Ohdo syndrome, SBBYS variant. To the best of our knowledge, this is the first reported case of Ohdo syndrome in the Philippines.

CASE REPORT

A 16-year-old Filipino female presented with intellectual disability and syndromic features. She was born full-term through normal spontaneous delivery to a healthy 35-year-old G3P3 mother. Her birthweight was approximately 2500 g. She had a poor cry and hypotonia at birth. The parents are non-consanguineous, and her two siblings are unaffected. No known family history of similar conditions was reported.

Postnatally, the patient exhibited marked blepharophimosis and ptosis. Developmental delays became apparent: she began walking at the age of 2 years but never developed speech. Though responsive to commands, she was unable to attend special education due to frequent tantrums. Psychological evaluation revealed an Intelligence quotient below 70, confirming intellectual disability. Menarche and secondary sexual development began at 14 but remain immature.

Her mother, an overseas worker in cyprus, sought information from rare disease networks and was advised to undergo genetic testing. Whole exome sequencing revealed a pathogenic KAT6B mutation, confirming Say–Barber– Biesecker–Young–Simpson (SBBYS) type Ohdo syndrome. The detailed genetic analysis reports were not available at the time of writing. Initial laboratories, including complete blood count, urinalysis, and thyroid function tests, were normal. A skeletal survey was requested to evaluate associated skeletal anomalies.

On physical examination [Figure 1], the patient had a stooped posture, joint laxity, blepharophimosis, ptosis, intermittent nystagmus, broad nasal bridge, rounded nose tip, micrognathia, long thumbs, single palmar crease, atrophic thenar/hypothenar muscles, stiff finger joints, and hallux valgus. A grade 3/6 holosystolic murmur and widely spaced teeth were also noted.

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Figure 1:

Physical examination findings reveal craniofacial and skeletal abnormalities, including (a) blepharophimosis (black arrow) and ptosis (white arrow), broad nasal bridge (black dashed arrow), (b) rounded nose tip (white arrow), micrognathia (black arrow), (c) relatively long thumbs (black arrows), single palmar crease (black dashed arrows), atrophic hypothenar (white asterisks) and thenar (black asterisks) muscles, and (d) large first toes (black arrows).

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Skeletal survey revealed micrognathia, scoliosis, and intact clavicles and ribs [Figure 2]. A proximally placed ulna indicated negative ulnar variance. The 2^nd digit distal phalanges were short with flexed distal interphalangeal joints; proximal interphalangeal joints of 2^nd and 3^rd fingers were hyperextended. Bone age was consistent with a 17-year-old female. The knees were unremarkable. Foot radiographs showed bilateral long 1^st metatarsals and hallux valgus [Figure 3].

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Figure 2:

Composite survey results of the axial skeleton. Radiographs of the (a) skull AP, and (b) thoracolumbar spine AP reveal abnormalities. Scoliosis was noted (white arrows).

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Figure 3:

Composite skeletal survey results of the appendicular skeleton. Radiographs of the (a) radius-ulna AP, (b) hands AP, and (c) feet APL reveal further generalized abnormalities. Notable findings include negative ulnar variance (white arrows in a) and bilateral hallux valgi deformity (white arrows in c).

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These radiologic findings are consistent with SBBYS-type Ohdo syndrome. The presence of normal patellae helped rule out genitopatellar syndrome [Table 1], which shares the same genetic etiology but includes absent patellae and genital anomalies. Magnetic resonance imaging (MRI) and panoramic dental imaging were recommended but not completed due to uncooperativeness. The patient was eventually lost to follow-up.

DISCUSSION

Ohdo syndrome was first reported in 1986 by Ohdo et al., who described two sisters with intellectual disability, congenital heart disease, ptosis, and dental anomalies.^[1] Several variants have since been described. The SBBYS variant, now recognized as a distinct clinical entity, was described in the late 1980s and early 1990s. It is characterized by blepharophimosis, midface hypoplasia, hypotonia, hyperextensible joints, dental anomalies, and intellectual disability.^[2]

In 2006, Verloes et al. proposed grouping blepharophimosis-mental retardation syndromes into five categories, with SBBYS being the most distinct and recognizable.^[3] It is caused by heterozygous mutations in KAT6B, a gene located on chromosome 10q22.2 that encodes a histone acetyltransferase involved in embryonic development.^[4,5] The MYST-type acetyltransferase domain of KAT6B regulates gene transcription through histone H3 acetylation at lysines 9 and 14, impacting skeletal, craniofacial, and neurologic development.

KAT6B plays a vital role in mesenchymal cell differentiation and osteoblast maturation, partly through its control of RUNX2, a master regulator of osteogenesis.^[6] Pathogenic variants, typically truncating mutations in the gene’s C-terminal region, impair normal protein interactions with co-regulators such as bromodomain and PHD finger-containing protein 1 (BRPF1), inhibitor of growth family member 5 (ING5), and MYST/Esa1-associated factor 6 (MEAF6). This dysregulation leads to phenotypic features such as scoliosis, hallux valgus, joint contractures, and distinctive craniofacial anomalies.^[7,8]

KAT6B mutations also disrupt neural crest cell migration, resulting in midface hypoplasia, micrognathia, and blepharophimosis. The condition may impair forkhead box L2 (FOXL2)-dependent eyelid separation in early fetal life.^[9] In the oral-maxillofacial region, panoramic imaging may show hypoplastic maxilla, delayed tooth eruption, and dental malocclusion. Cephalometric analysis may reveal Class III skeletal relationships.

KAT6B is expressed in fetal brain tissue, including the ventricular zone, explaining the intellectual disability. Patients may have global developmental delay, hypotonia, and behavioral disturbances. Diagnostic workup typically includes genetic testing (e.g., whole exome sequencing) and supporting radiologic studies.

Clinical diagnostic criteria for SBBYS include mandatory findings: (1) blepharophimosis, (2) ptosis, and (3) intellectual disability.^[10] Supporting features include hypotonia, hypoplastic teeth, undescended testes, midface hypoplasia, and skeletal anomalies. The presence of two major features or one major and two minor features should prompt testing for KAT6B mutations.

DIFFERENTIAL DIAGNOSIS

Such clinical and radiologic findings supported a diagnosis of Ohdo syndrome. The presence of normal patellae in this patient made the diagnosis of genitopatellar syndrome unlikely. Other differentials include Kabuki syndrome, Smith-Lemli-Opitz syndrome, and Cornelia de Lange syndrome, which share overlapping features such as intellectual disability, facial dysmorphism, and skeletal anomalies [Table 1]. However, there was an absence of characteristic findings such as vertebral anomalies and hip dislocation (in Kabuki syndrome), postaxial polydactyly and short long bones (in Smith-Lemli-Opitz syndrome), and micromelia and vertebral segmentation defects (in Cornelia de Lange syndrome).

CONCLUSION

In this case, a skeletal survey confirmed multiple typical findings and ruled out genitopatellar syndrome. Although KAT6B mutations underlie both conditions, genitopatellar syndrome presents with additional features such as agenesis of the corpus callosum, genital abnormalities, and absent patellae. Our patient had normal patellae and no noted genital anomalies. MRI, echocardiography, and thyroid function testing are helpful adjuncts. In this case, a holosystolic murmur suggested a possible septal defect, which is commonly associated with the syndrome. Unfortunately, echocardiography was not performed due to noncooperation. No curative treatment exists for KAT6B-related disorders. Management is multidisciplinary and supportive.

TEACHING POINTS

• KAT6B-related disorders such as Say–Barber–Biesecker– Young–Simpson (SBBYS) syndrome can be differentiated from genitopatellar syndrome by key skeletal findings, such as the presence or absence of patellae and characteristic craniofacial and digital anomalies.

• The presence of subtle but specific hand and foot anomalies, such as long thumbs, single palmar crease, and bilateral hallux valgus, can offer early diagnostic clues in syndromic intellectual disability, even before genetic confirmation.

MCQs

1. What is the genetic basis of both Say–Barber–Biesecker– Young–Simpson and Genitopatellar syndromes?

   1. Trisomy 18

   2. Mutations in RUNX2

   3. Mutations in KAT6B

   4. Methylation defects on 15q11

   Answer key: c

2. Which of the following features best distinguishes Say– Barber–Biesecker–Young–Simpson (SBBYS) syndrome from Genitopatellar syndrome, despite both being caused by KAT6B mutations?

   1. Intellectual disability

   2. Hypoplastic teeth

   3. Normal patellae

   4. Blepharophimosis

   Answer key: c

3. Which of the following best explains the craniofacial and skeletal anomalies seen in KAT6B-related disorders?

   1. Failure of neural tube closure during neurulation

   2. Impaired collagen cross-linking in bone matrix

   3. Disruption of histone acetylation during organogenesis

   4. Abnormal migration of neural crest cells due to cilia defects

   Answer key: c