Autosomal dominant craniometaphyseal dysplasia (AD-CMD) is characterized by progressive diffuse hyperostosis of cranial bones evident clinically as wide nasal bridge, fullness of the paranasal tissue, hypertelorism with an increase in bizygomatic width, and prominent mandible. Development of dentition may be delayed and teeth may fail to erupt as a result of hyperostosis and sclerosis of alveolar bone. Progressive thickening of craniofacial bones continues throughout life, often resulting in narrowing of the cranial foramina, including the foramen magnum. If untreated, compression of cranial nerves can lead to disabling conditions such as facial palsy, blindness, or deafness (conductive and/or sensorineural). In individuals with typical uncomplicated AD-CMD life expectancy is normal; in those with severe AD-CMD life expectancy can be reduced as a result of compression of the foramen magnum. Diagnosis is based on clinical and radiographic findings that include diffuse hyperostosis of the cranial base, cranial vault, facial bones, and mandible as well as widening and radiolucency of metaphyses in long bones. Identification of a heterozygous pathogenic variant in ANKH by molecular genetic testing can confirm the diagnosis if clinical features are inconclusive. Treatment of manifestations: Treatment for feeding and respiratory issues per craniofacial team; surgical intervention to reduce compression of cranial nerves and the brain stem / spinal cord at the level of the foramen magnum. Severely overgrown facial bones can be contoured; however, surgical procedures can be technically difficult and bone regrowth is common. Hearing aids; vision aids and surgical treatment for optic nerve impaction; speech therapy; surgical intervention for malocclusion. Surveillance: Evaluation for feeding and respiratory issues at least annually; neurologic evaluation for signs and symptoms of narrowing of the cranial foramina including the foramen magnum at least annually; hearing and ophthalmologic assessment at least annually. Evaluation of relatives at risk: It is appropriate to evaluate relatives at risk in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures; early diagnosis of at-risk relatives may be beneficial for management of complications from progressive hyperostosis. By definition, AD-CMD is inherited in an autosomal dominant manner. Most individuals diagnosed with AD-CMD have an affected parent. The proportion of individuals with AD-CMD caused by a de novo pathogenic variant is approximately 30%. Each child of an individual with AD-CMD has a 50% chance of inheriting an AD-CMD-related pathogenic variant. Once the AD-CMD-related pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

We describe a case of craniometaphyseal dysplasia (CMD) that was initially misdiagnosed as craniodiaphyseal dysplasia (CDD). CMD and CDD are both rare genetic disorders affecting the craniofacial and tubular bones, due to ANKH and SOST gene mutations, respectively, causing similar defects in the control of bone mineralisation.The patient is male, who has been followed longitudinally from birth to his mid-teens, touching on important milestones concerning misdiagnosis and management of CMD. We discuss relevant investigations, diagnosis of ANKH mutation on genetic testing and neurosurgical management, as the patient successfully underwent foramen magnum decompression for secondary Chiari I malformation. We refer to the patient as 'proband' as he is the first in his family diagnosed with a genetic condition.This study highlights the importance of correct identification of the underlying diagnosis as this can affect management. Surgical intervention can be challenging but can successfully manage life-threatening complications of this condition.

Autosomal dominant craniometaphyseal dysplasia (AD-CMD) is a rare condition defined by the occurrence of progressive diffuse hyperostosis of cranial bones and abnormal metaphyseal widening of the tubular bones. ANKH is known to be the only gene associated with AD-CMD. We present a case of a toddler boy with macrodolichocephaly, asymmetry of the skull, wide bulging forehead, gingival hypertrophy and irregular teeth. Physical examination, X-ray and DNA analysis were performed. All exons and flanking intron regions of ANKH were amplified by PCR and directly sequenced using the Sanger method. X-ray images showed diffuse osteosclerosis in the area of facial skeleton and skull base. Limbs exhibited club-shaped enlargement of the distal metaphysis of the femur and the proximal metaphysis of the tibia were described. The DNA analysis showed that the patient is a heterozygous carrier of the known pathogenic in-frame deletion (rs121908406; ANKH:c.1122-4delCTC, p.Ser375del), which has already been described in patients with AD-CMD.

Pathogenic ANKH variants are a known cause of chondrocalcinosis (Online Mendelian Inheritance in Man [OMIM] #118600) and craniometaphyseal dysplasia (OMIM #123000). Here, we describe the phenotype and genotype of autosomal dominant infantile epilepsy caused by a c.-11C>T change upstream of the gene's normal ATG initiation codon of ANKH in a family of southern Italian descent; we correlate the phenotype with known epilepsy syndromes and provide the first evidence of recurrence of this particular ANKH variant. Phenotyping and genotyping (short-read exome/genome sequencing) was performed on six members of a family with self-limited familial infantile epilepsy (SeLFIE). We describe a family with six individuals who presented with infantile onset epilepsy. All affected family members experienced focal and/or bilateral tonic-clonic seizures, sometimes triggered by fever or infection, with seizure onset predominantly before the age of 2 years. Patients responded well to antiseizure medication, and seizures resolved completely before the age of 4 years. Short-read genome/exome sequencing and comparative bioinformatic analysis of the variants of five affected individuals and one unaffected individual revealed ANKH c.-11C>T as the causative pathogenic variant in this family, segregating with the disease. To our knowledge, we report the second family with autosomal dominant epilepsy caused by an ANKH c.-11C>T variant. The pediatric phenotype closely resembles that of the previously reported British family, suggesting low phenotypic heterogeneity, and aligns with SeLFIE. ANKH-associated epilepsy should be considered in SeLFIE, especially in cases with a family history of chondrocalcinosis or recurrent acute joint pain episodes.

Osteosclerotic bone diseases include more than 30 rare diseases characterized by excessive bone formation. The aim of this study is to compare the molecular pathogenesis and prognostic features of 12 different osteosclerotic diseases. Thirty-four patients from 23 families were included, 25 of whom were followed for a period of one to 22 years. Exome sequencing was performed in 20 families. Primary hypertrophic osteoarthropathy (PHOAR1/2) was found in 12 patients, followed by juvenile Paget's disease (JPD)-5 in five, craniometaphyseal dysplasia (CMD) and Camurati-Engelmann disease (CED) in four, Ghosal hematodiaphyseal dysplasia (GHDD) in three patients, sclerosteosis-1 in two patients, and ultra-rare diseases including trichothiodystrophy-1, prenatal Caffey disease, melorheosteosis, and Lenz-Majewski hyperostotic dwarfism in one patient each. Patients with CMD and sclerosteosis-1 had severe cranial sclerosis leading to facial dysmorphism. CMD was characterized by metaphyseal widening, radiolucency, and diaphyseal sclerosis of the long bones in early childhood and later developed Erlenmeyer flask deformity sparing the vertebrae and pelvis, whereas sclerosteosis-1 manifested as generalized sclerosis. CED and GHDD share bone pain, difficulty in walking, and diaphyseal sclerosis, with some patients also having bone marrow involvement. Interestingly, patients with CED and JPD-5 showed osteopenia in early childhood, followed by the development of osteosclerosis in late childhood. Clinical and radiologic findings improved over time in PHOAR1 patients, whereas they progressed in JPD-5 and trichothiodystrophy-1 patients. Intra- and interfamilial clinical differences were observed in CMD, CED, JPD-5, and GHDD. The knowledge gained about the natural history of osteosclerotic diseases will make an important contribution to their diagnosis and management.