Cartilage hair hypoplasia-anauxetic dysplasia (CHH-AD) spectrum disorders are rare skeletal dysplasias caused by pathogenic variants in RMRP, associated with immune dysfunction and cancer predisposition. While non-Hodgkin lymphoma is more commonly seen, Hodgkin lymphoma (HL) is rarely reported, and its management in this setting remains unclear. We describe 2 siblings with genetically confirmed CHH-AD who developed relapsed/refractory EBV-positive classic HL. Both presented with short stature, atopy, recurrent infections, and elevated IgE. The brother was diagnosed with stage IV disease, and the sister with stage IIB. Despite receiving frontline chemotherapy, both relapsed within a year. Salvage therapy with gemcitabine/vinorelbine induced metabolic responses, followed by radiotherapy and consolidation with brentuximab vedotin. Autologous transplant was considered but declined by the family due to perceived risks. At 30 months follow-up, both remain in complete remission. Genetic testing confirmed a shared homozygous pathogenic RMRP variant. These cases expand the oncologic spectrum of CHH-AD to include HL, highlight the risk of aggressive disease and early relapse, and demonstrate that durable remission may be achieved without transplantation when consolidation with targeted therapy is feasible. Early recognition of CHH-AD features in HL patients may allow risk-adapted therapy and informed genetic counseling. The cartilage-hair hypoplasia – anauxetic dysplasia (CHH-AD) spectrum disorders are a continuum that includes the following phenotypes: Metaphyseal dysplasia without hypotrichosis (MDWH). Cartilage-hair hypoplasia (CHH). Anauxetic dysplasia (AD). CHH-AD spectrum disorders are characterized by severe disproportionate (short-limb) short stature that is usually recognized in the newborn, and occasionally prenatally because of the short extremities. Other findings include joint hypermobility, fine, silky hair, immunodeficiency, anemia, increased risk for malignancy, gastrointestinal dysfunction, and impaired spermatogenesis. The most severe phenotype, AD, has the most pronounced skeletal phenotype, may be associated with atlantoaxial subluxation in the newborn, and may include cognitive deficiency. The clinical manifestations of the CHH-AD spectrum disorders are variable, even within the same family. Diagnosis of a CHH-AD spectrum disorder is established in a proband with characteristic clinical and radiographic findings. If clinical and radiographic findings are inconclusive, identification of biallelic pathogenic variants in RMRP by molecular genetic testing can confirm the diagnosis and allow for family studies. Treatment of manifestations: If cervical spinal instability is identified in a person with AD, special care is required during general anesthesia; surgery may be needed to fuse unstable cervical vertebrae and/or to treat progressive kyphoscoliosis that compromises lung function in AD; corrective osteotomies may be required for progressive varus deformity of the lower extremities; treatment of underlying infections based on their type, location, and severity; immediate high-dose intravenous acyclovir for varicella infection; consideration of prophylactic antibiotic therapy and/or immunoglobulin replacement therapy; recurrent severe infections, severe combined immunodeficiency (SCID), and/or severely depressed erythropoiesis may warrant hematopoietic stem cell transplantation; physiotherapy and other acute and long-term medical management for bronchiectasis per pulmonologist; red blood cell transfusions for severe anemia with iron chelation as needed; standard treatments for malignancies, congenital megacolon, Hirschsprung disease, and intestinal malabsorption; nutritional evaluation in those with short bowel syndrome; hormonal induction as needed for pubertal maturation; developmental and educational support as needed. Surveillance: Monitor growth using CHH-specific growth curves; clinical and (if warranted) radiographic examination of joints of the lower extremities and spine annually in childhood and as required in adulthood; annual clinical and radiographic examination of the spine in individuals with AD. Monitor all children regardless of immune status during the first two years of life for recurrent infections, especially life-threatening varicella infection, then monitor annually; laboratory assessment for those with suspected infection; laboratory assessment of immune function with frequency based on initial lab results; assess the frequency of respiratory tract infections at each visit; high-resolution CT examination for those with suspected bronchiectasis and lung MRI to monitor bronchiectasis. For those who have not had anemia, observe for clinical signs of anemia; for those in remission after treatment, complete blood count every six months. Clinical and laboratory examination for manifestations of malignancy annually in children and as needed in adults; abdominal ultrasound every one to two years in children and as needed in adults. Assess pubertal development annually throughout adolescence; assess for hypogonadism in those with pubertal delay. Developmental and cognitive assessment as needed in those with AD throughout childhood. Agents/circumstances to avoid: Administration of live vaccines when signs of abnormal immunologic function or SCID are present. Evaluation of relatives at risk: Early diagnosis of relatives at risk for the CHH-AD spectrum disorders allows for early management of manifestations that can be associated with significant morbidity (e.g., infections, immunization with live vaccines, malignancies). Pregnancy management: Fetal growth is generally unaffected; therefore, planned cesarean section should be considered in term pregnancies in affected women due to cephalopelvic disproportion. CHH-AD spectrum disorders are inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an RMRP pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the RMRP pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and molecular genetic prenatal and preimplantation genetic testing for CHH-AD spectrum disorders are possible.

The biallelic variants of the POP1 gene are associated with the anauxetic dysplasia (AAD OMIM 607095), a rare skeletal dysplasia, characterized by prenatal rhizomelic shortening of limbs and generalized joint hypermobility. Affected individuals usually have normal neurodevelopmental milestones. Here we present three cases from the same family with likely pathogenic homozygous POP1 variant and a completely novel phenotype: a girl with global developmental delay and autism, microcephaly, peculiar dysmorphic features and multiple congenital anomalies. Two subsequent pregnancies were terminated due to multiple congenital malformations. Fetal DNA samples revealed the same homozygous variant in the POP1 gene. Expression of the RMRP was reduced in the proband compared with control and slightly reduced in both heterozygous parents, carriers for this variant. To our knowledge, this is the first report of this new phenotype, associated with a novel likely pathogenic variant in POP1. Our findings expand the phenotypic spectrum of POP1-related disorders.

Cartilage-hair hypoplasia (CHH, OMIM # 250250) is a rare autosomal recessive disorder, which includes cartilage-hair hypoplasia-anauxetic dysplasia (CHH-AD) spectrum disorders. CHH-AD is caused by homozygous or compound heterozygous mutations in the RNA component of the mitochondrial RNA-processing Endoribonuclease (RMRP) gene. Here, we report 2 cases of Korean children with CHH-AD. In the first case, the patient had metaphyseal dysplasia without hypotrichosis, diagnosed by whole exome sequencing (WES), and exhibited only skeletal dysplasia and lacked extraskeletal manifestations, such as hair hypoplasia and immunodeficiency. In the second case, the patient had skeletal dysplasia, hair hypoplasia, and immunodeficiency, which were identified by WES. The second case is the first CHH reported in Korea. The patients in both cases received regular immune and lung function checkups. Our cases suggest that children with extremely short stature from birth, with or without extraskeletal manifestations, should include CHH-AD as a differential diagnosis. Clinical suspicion is the most important and RMRP sequencing should be considered for the diagnosis of CHH-AD.

The cartilage hair hypoplasia and anauxetic dysplasia (CHH-AD) spectrum encompasses a group of rare skeletal disorders, with anauxetic dysplasia (ANXD) at the most severe end of the spectrum. Biallelic variants in RMRP, POP1, and NEPRO (C3orf17) have previously been associated with the three currently recognized ANXD types. Generally, all types are characterized by severe short stature, brachydactyly, skin laxity, joint hypermobility and dislocations, and extensive skeletal abnormalities visible on radiological evaluation. Thus far, only five patients with type 3 anauxetic dysplasia (ANXD3) have been reported. Here, we describe one additional ANXD3 patient. We provide a detailed physical and radiological evaluation of this patient, in whom we identified a homozygous variant, c.280C > T, p.(Arg94Cys), in NEPRO. Our patient presented with clinically relevant features not previously described in ANXD3: atlantoaxial subluxation, extensive dental anomalies, and a sagittal suture craniosynostosis resulting in scaphocephaly. We provide an overview of the literature on ANXD3 and discuss our patient's characteristics in the context of previously described patients. This study expands the phenotypic spectrum of ANXD, particularly ANXD3. Greater awareness of the possibility of atlantoaxial subluxation, dental anomalies, and craniosynostosis may lead to more timely diagnosis and treatment.