Microcephalic primordial dwarfing syndromes (Majewski osteodysplastic primordial dwarfism [MOPD II], Seckel syndrome, MOPD I/III [Taybi-Linder syndrome])

Microcephalic primordial dwarfing syndromes are a group of rare genetic disorders characterized by severe pre- and postnatal growth restriction and marked microcephaly, often accompanied by distinctive facial features, skeletal abnormalities, and developmental or intellectual impairment. The group is genetically heterogeneous and includes Majewski osteodysplastic primordial dwarfism type II (MOPD II), MOPD I/III (Taybi-Linder syndrome), and genetically heterogeneous forms of Seckel syndrome. These conditions are generally inherited in an autosomal recessive manner, so absence of a relevant family history does not exclude the diagnosis.

Neurodevelopmental manifestations vary substantially between disorders. MOPD II is particularly notable for ADHD and learning difficulties, while intellectual development is often in the normal-to-borderline range unless cerebrovascular disease has occurred. MOPD I/III is associated with severe neurologic impairment, developmental disability, and often early mortality. Seckel syndrome is heterogeneous, with intellectual, neurodevelopmental, and neurologic manifestations varying according to the underlying genetic cause. A distinctive presentation may include the combination of severe microcephaly, extreme short stature, and characteristic facial and skeletal abnormalities.

They can present with psychiatric features such as ADHD, hyperactivity, behavioral difficulties, and anxiety, particularly in MOPD II. MOPD II is particularly notable for ADHD and learning difficulties, whereas MOPD I/III is generally associated with severe neurologic impairment and developmental disability. Seckel syndrome may also be associated with intellectual impairment, seizures, and behavioral difficulties, although the phenotype varies according to the underlying genetic cause.

From a morphologic lens perspective, other features include (but are not limited to):

• Microcephaly

• Malar flattening

• Midface retrusion

• Micrognathia

• Downslanted palpebral fissures

• Proptosis

• Low-set ears

• Absent (ear)lobes (in Seckel syndrome)

• Prominent nasal bridge

• Clinodactyly of fifth fingers

• Single transverse palmar crease

Other characteristic features include skeletal dysplasia and abnormal dentition, particularly in MOPD II. Neurologic manifestations may include seizures/epilepsy and structural brain abnormalities, including abnormalities of the corpus callosum and cerebral cortex in MOPD I/III. MOPD II is distinguished by a particularly important risk of systemic vascular disease, including moyamoya vasculopathy and intracranial aneurysms, as well as coronary and renal vascular disease. Additional reported features across the group include hypertension, insulin resistance or diabetes, hearing and visual abnormalities, feeding difficulties, gastrointestinal abnormalities, genitourinary abnormalities, and hematologic abnormalities.

Early diagnosis is important to identify and monitor potentially serious neurologic, cerebrovascular, cardiac, renal, endocrine, and developmental complications, recognize neuropsychiatric needs early, and institute tailored multidisciplinary surveillance and treatment. In MOPD II, surveillance for cerebrovascular disease is particularly important because moyamoya vasculopathy and intracranial aneurysms can lead to stroke and other serious complications.