TWIST related disorders in two Mongolian adolescents: case reports and review of the literature
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical- Pediatric
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Secondary Categories:
- Clinical- Pediatric
Introduction
Sweeney-Cox syndrome (SWCOS), Barber–Say syndrome (BBRSAY), and ablepharon macrostomia syndrome (AMS) are rare autosomal dominant craniofacial syndromes with overlapping clinical features associated with pathogenic variants in the TWIST genes.
Clinical findings of SWCOS include hypertelorism, upper eyelid coloboma, skull and facial bone abnormalities, cleft palate, and low-set cupped ears. SWCOS is due to heterozygous missense variants in the TWIST1 gene that affect the glutamic residue at position 117 of the TWIST1 protein (p.Glu117Val and p.Glu117Gly).
Clinical findings of BBRSAY include severe hypertrichosis especially of the back, eyelid deformities, macrostomia, abnormal and low-set ears, and low frontal hairline. Cognitive outcome is variable. Clinical findings of AMS include sparse hair, absent eyelids, microtia, macrostomia, poor growth, and variable abnormalities of the nipples, genitalia, and digits. Cognitive outcome is largely normal. BBRSAY and AMS are both due to heterozygous missense variants in TWIST2 gene that affect the glutamic residue at position 75 of the TWIST2 protein (BBRSAY - p.Glu75Ala and p.Glu75Gln; AMS - p.Glu75Lys).
Case Presentation
Patient 1 is a 12 year old female with clinical findings of SWCOS. Striking facial findings include coloboma of the upper eyelid bilaterally, hypertelorism, flat nasal bridge, underdeveloped nasal alae, and long face with a broad forehead and pointed chin. Syndactyly of the third and fourth fingers and third and fourth toes we noted. She has appropriate development and educational achievement. Her mother is noted to have similar facial features. Family history is otherwise noncontributory.
Patient 2 is an 11 year old male with clinical findings of BBRSAY and AMS. Striking facial findings include absent medial upper eye lashes, sparse lower eye lashes, long palpebral fissures, sparse eyebrows particularly laterally, hypertelorism, high nasal root, wide philtrum, wide mouth with downturned corners, and low set ears with left ear with simple helical morphology. He is noted to have congenital left sided hearing loss. Dermatologic findings include congenital hypertrichosis in an S-shape curvature covering the back (most prominent on the lower back) Blaschkolinear dyspigmentation (primarily of the thorax and upper arms), and hypoplastic nipples. He does not have scoliosis.
Other findings include fecal incontinence, hypospadias, congenital hypothyroidism treated with L-thyroxine by 1 month of age, mild myopia, and mild intellectual disability. There are no other family members with similar facial features, dermatological findings, or cognitive issues. Mother was diagnosed with right sided hearing loss at age 11. Family history is otherwise noncontributory.
Diagnostic Workup
Using OMIM and comparison with previously reported cases in the medical literature review, we arrived at clinical diagnoses. Molecular genetic testing has not been obtained.
Treatment and Management
Based on the clinical diagnoses, supportive and symptomatic care was continued.
Outcome and Follow-Up
Given our clinical diagnoses, we can prepare the medical team and family for anticipated medical issues, surgical options, and reproductive risks.
Discussion
SWCOS, BBRSAY, and AMS are rare and under recognized genetic conditions. These patients add to the published information regarding the clinical findings, developmental issues, and health issues associated with these conditions.
Conclusion
The diagnosis in our two patients remains solely clinical as the availability of molecular genetic testing in Mongolia is very limited. These cases illustrate the ongoing need for accurate phenotyping and clinical diagnosis in areas with limited genetic resources. The cases also illustrate the need for ongoing international collaboration amongst geneticists to inform local medical teams and government representatives regarding resource allocation needed to allow patients and families access to appropriate phenotype-driven clinical molecular testing.
Sweeney-Cox syndrome (SWCOS), Barber–Say syndrome (BBRSAY), and ablepharon macrostomia syndrome (AMS) are rare autosomal dominant craniofacial syndromes with overlapping clinical features associated with pathogenic variants in the TWIST genes.
Clinical findings of SWCOS include hypertelorism, upper eyelid coloboma, skull and facial bone abnormalities, cleft palate, and low-set cupped ears. SWCOS is due to heterozygous missense variants in the TWIST1 gene that affect the glutamic residue at position 117 of the TWIST1 protein (p.Glu117Val and p.Glu117Gly).
Clinical findings of BBRSAY include severe hypertrichosis especially of the back, eyelid deformities, macrostomia, abnormal and low-set ears, and low frontal hairline. Cognitive outcome is variable. Clinical findings of AMS include sparse hair, absent eyelids, microtia, macrostomia, poor growth, and variable abnormalities of the nipples, genitalia, and digits. Cognitive outcome is largely normal. BBRSAY and AMS are both due to heterozygous missense variants in TWIST2 gene that affect the glutamic residue at position 75 of the TWIST2 protein (BBRSAY - p.Glu75Ala and p.Glu75Gln; AMS - p.Glu75Lys).
Case Presentation
Patient 1 is a 12 year old female with clinical findings of SWCOS. Striking facial findings include coloboma of the upper eyelid bilaterally, hypertelorism, flat nasal bridge, underdeveloped nasal alae, and long face with a broad forehead and pointed chin. Syndactyly of the third and fourth fingers and third and fourth toes we noted. She has appropriate development and educational achievement. Her mother is noted to have similar facial features. Family history is otherwise noncontributory.
Patient 2 is an 11 year old male with clinical findings of BBRSAY and AMS. Striking facial findings include absent medial upper eye lashes, sparse lower eye lashes, long palpebral fissures, sparse eyebrows particularly laterally, hypertelorism, high nasal root, wide philtrum, wide mouth with downturned corners, and low set ears with left ear with simple helical morphology. He is noted to have congenital left sided hearing loss. Dermatologic findings include congenital hypertrichosis in an S-shape curvature covering the back (most prominent on the lower back) Blaschkolinear dyspigmentation (primarily of the thorax and upper arms), and hypoplastic nipples. He does not have scoliosis.
Other findings include fecal incontinence, hypospadias, congenital hypothyroidism treated with L-thyroxine by 1 month of age, mild myopia, and mild intellectual disability. There are no other family members with similar facial features, dermatological findings, or cognitive issues. Mother was diagnosed with right sided hearing loss at age 11. Family history is otherwise noncontributory.
Diagnostic Workup
Using OMIM and comparison with previously reported cases in the medical literature review, we arrived at clinical diagnoses. Molecular genetic testing has not been obtained.
Treatment and Management
Based on the clinical diagnoses, supportive and symptomatic care was continued.
Outcome and Follow-Up
Given our clinical diagnoses, we can prepare the medical team and family for anticipated medical issues, surgical options, and reproductive risks.
Discussion
SWCOS, BBRSAY, and AMS are rare and under recognized genetic conditions. These patients add to the published information regarding the clinical findings, developmental issues, and health issues associated with these conditions.
Conclusion
The diagnosis in our two patients remains solely clinical as the availability of molecular genetic testing in Mongolia is very limited. These cases illustrate the ongoing need for accurate phenotyping and clinical diagnosis in areas with limited genetic resources. The cases also illustrate the need for ongoing international collaboration amongst geneticists to inform local medical teams and government representatives regarding resource allocation needed to allow patients and families access to appropriate phenotype-driven clinical molecular testing.