Syndromes for Monday, April 7th, 2025

History

Patient is a term 2 month old male presenting with poor tone, respiratory distress, coarse facial features, and failure to thrive.

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Question

What is the finding?

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Correct answer

Accelerated or advanced bone maturation due to an underlying overgrowth syndrome.

Discussion

This patient has Marshall-Smith Syndrome (MSS), a rare autosomal dominant malformation syndrome caused by a de novo heterozygous mutation in the nuclear factor I/X gene (NFIX) on chromosome 19p13. It is estimated there are about 57 reported cases worldwide as of 2020.

Genetic testing is the definitive diagnosis for MSS. 

MSS is characterized by multiorgan malformations; however, a key feature of MSS is accelerated skeletal maturation with a bone age of up to 4 at birth. In this patient, their bone age at 2 months old corresponded to that of a 2 year old male.

Other features of MSS are:

• Facial features: low-set ears, prominent forehead, micrognathia/retrognathia, flat nasal bridge
• Cardiovascular: atrial septal defect, patent ductus arteriosus
• Respiratory: choanal stenosis or atresia, laryngomalacia, pulmonary hypertension, apnea
• Abdomen: umbilical hernia, omphalocele
• MSK: bone age of 4 at birth, short sternum, pectus excavatum, large sternal ossification centers, wide proximal and middle phalanges, distal widening of metacarpals
• Neurologic: intellectual disability, hypotonia, cerebral atrophy, absent corpus callosum, spinal stenosis

Management of patients with MSS often target these clinical presentations, and include, but not limited to, tracheotomy, gastrostomy, and IV antibiotics for recurrent pneumonia. There is no specific treatment for the advanced bone age.

Differential diagnosis

Differential diagnosis includes overgrowth syndromes, such as:

• Weaver syndrome: patients tend to be overweight
• Sotos syndrome: normal to mild intellectual disability, BMI is not low
• Perlman syndrome: associated with Wilms tumor
• Malan syndrome: overgrowth, less severe developmental and intellectual disability, also associated with a mutation in the NFIX gene

References

• Buchanan EP. Syndromes with craniofacial abnormalities. In: UpToDate, Connor RF (Ed), Wolters Kluwer. (Accessed on March 8, 2025.)
• Mulder PA, van Balkom IDC, Landlust AM, et al. Development, behaviour and sensory processing in Marshall-Smith syndrome and Malan syndrome: phenotype comparison in two related syndromes. J Intellect Disabil Res. 2020;64(12):956-969. doi:10.1111/jir.12787
• Online Mendelian Inheritance in Man, OMIM. Johns Hopkins University, Baltimore, MD. MIM Number: 602535:10/31/2023. World Wide Web URL: https://omim.org/
• Padilla ER, Rogol AD. The child with tall stature and/or abnormally rapid growth. In: UpToDate, Connor RF (Ed), Wolters Kluwer. (Accessed on March 8, 2025.)