Juvenile Alexander Disease and Cleidocranial Dysplasia: A Rare Combination of Genetic Abnormalities in a Pediatric Patient

Abstract

Cleidocranial dysplasia (CCD) and Alexander disease (AxD) are rare, autosomal dominant disorders that are characterized by a mutation in the runt-related transcription factor 2 (RUNX2) and the glial fibrillary acidic protein (GFAP) genes, respectively. There is no known relationship between RUNX2 and GFAP which would cause co-morbidity. We report a rare case of a 13-year-old with CCD who came to the clinic complaining of a 2-year history of progressively worsening episodic exacerbations of bulbar, ataxia, nystagmus, kyphoscoliosis, and nausea, but was intact cognitively. Initial diagnosis was a difficult process because preliminary symptoms for Juvenile AxD overlapped with previously diagnosed CCD and the initial genetic test identified our patient’s GFAP gene as a variant of uncertain significance. Our experience emphasizes the importance of continuing to report pathogenic variants of GFAP for AxD to build on our existing compendium of variants for GFAP for quicker and more efficient diagnosis of AxD.

Introduction

Cleidocranial dysplasia (CCD) is an autosomal dominant skeletal disease that has varying phenotypes, characterized by inherited or de novo mutations in the runt-related transcription factor 2 (RUNX2) gene. ¹ Patients with RUNX2 gene mutations often present with open or delayed closure of calvarial sutures, hypoplastic or aplastic clavicles, dentition anomalies, and supernumerary teeth. ² Though early recognition is essential for successful therapy and treatment, there is wide variability in the presentation of skeletal and extraosseous symptoms and many cases are misdiagnosed. Alexander disease (AxD) is a rare, autosomal dominant neurodegenerative disorder that is caused by a pathogenic gain-of-function variant in the glial fibrillary acidic protein (GFAP) gene. ³ AxD is predominantly seen in patients <2 years of age. It is a leukodystrophy characterized by the accumulation of GFAP-rich proteins in astrocytes, which cause the characteristic formation of Rosenthal fibers (RFs) in the subpial, perivascular, and subependymal regions of the cortex and white matter. ⁴ These have also been recently linked to aberrant Ca2+ responses in astrocytes. ⁵ Current research also suggests that genetic anticipation may occur in familial AxD and genetic mosaicism could explain this phenomenon. ⁶ We examine a 13-year old male with confirmed genetic diagnoses of both CCD and AxD. To date, there is no known relationship between RUNX2 and GFAP which would cause co-morbidity of both disorders. However, in one study of cultured neocortical astrocytes, RUNX2 protein was markedly expressed in cells expressing GFAP, with selective localization in the nucleus. ⁷ The relationship remains unclear.

Case Report

A 13-year-old with cleidocranial dysplasia, vitamin D deficiency, seasonal allergies, and lab-negative celiac disease. The patient was diagnosed clinically with cleidocranial dysplasia at birth with absent clavicles, mild macrocephaly, mild hypertelorism, and a high-arched palate. At this time, the CCD diagnosis was not genetically confirmed. Initially, the patient presented with 2 years of episodic dizziness, nausea, and choking. The initial frequency was every 4 to 6 months but progressively increased to every 2 to 4 months. The duration of episodes ranged from hours to 3 to 4 days. At baseline, he was not able to lay flat on his back since early childhood. The neurological examination was notable for mild dysarthria and dysphonia, originally thought to be baseline from his CCD, directional changing nystagmus, kyphoscoliosis, hyporeflexia, and a wide-based gait. An MRI of the brain without and with contrast found extensive nodular signal abnormality and enhancement involving the pons, medulla, and bilateral middle cerebellar peduncles (see Figure 1). Extensive confluent signal abnormality involved the periventricular white matter and bilateral basal ganglia. These results prompted an extensive workup for neuroimmunological, oncological, rheumatologic, infectious, nutritional, and genetic etiology. Cerebellar biopsy consisted of neutrophils with extensive Rosenthal fibers, reactive gliosis, eosinophilic granular bodies, and focal perivascular lymphocytic cuffing. There was no mitotic activity or necrosis identified. The presence of Rosenthal fibers prompted the treatment team to offer genetic testing through a next-generation sequencing panel for leukodystrophies and leukoencephalopathy at a commercial laboratory, which tested 446 genes. The parents also agreed to concurrently confirm the CCD diagnosis through genetic testing. Results confirmed that the patient had CCD with a RUNX2Exon 4 c.577C>T (p.Arg193*) pathogenic variant. Initially, the commercial laboratory classified the patient’s GFAP variant (GFAP c.1126 C>G (p.Arg376Gly)) as a variant of uncertain significance. After infectious and oncologic etiologies were ruled out and his bone health examined, he was trialed on high-dose steroids with a 7-week taper while waiting for genetic results. Symptoms resolved with the steroid trial, including the patient’s chronic inability to lay flat. However, no changes were seen on MRI while he was on steroids. Periodic coughing and choking returned as the patient’s steroids were tapered and completed. Two years after the initial onset of bulbar symptoms, the patient was admitted for an inability to swallow, a G-tube was placed, and he was initiated on a 5-day course of pulse steroids, which provided some improvement. Although the patient’s genetic results classified his GFAP gene mutation as a variant of uncertain significance, based on the clinical presentation, MRI, and biopsy, the treatment team felt the clinical presentation was significant enough to render a diagnosis of juvenile Alexander Disease. A few weeks later the genetic testing laboratory notified the team that the variant was reclassified as pathogenic with heterozygosity of a de novo GFAP mutation at c. 1126C>G (p.Arg376Gly).^8,9 The commercial laboratory reclassified the variant because of a re-review of the evidence in light of new variant interpretation guidelines. Parental testing was completed and showed that neither parent carried the GFAP variant, indicating that this variant most likely occurred de novo. Following this diagnosis, our patient was being considered for a clinical trial testing antisense oligonucleotide (ASO) treatment targeting GFAP, which has been shown in some models to ameliorate histological and behavioral abnormalities. ¹⁰

Figure 1.

T2-weighted axial MRI sections of the patient’s brain show extensive nodular signal abnormalities and enhancement involving the pons, medulla, and bilateral middle cerebellar peduncles. There is also extensive confluent signal abnormalities involving the periventricular matter and bilateral basal ganglia.

Discussion

By themselves, CCD and juvenile AxD are rare genetic disorders. In this case, overlapping features of scoliosis, mild dysarthria, and dysphonia made the diagnosis even more elusive. A brief review of the literature showed that the co-occurrence of 2 genetic disorders for skeletal deformities is well documented. ¹¹ For example, Liu et al ¹¹ found that patients with dual molecular diagnosis presented blended phenotypes of the 2 diseases, which greatly benefited from exome sequencing. Günthner et al ¹² presented a case that used whole exome sequencing to serve as a powerful instrument to determine 2 independent genetic pathologies. Balci et al ¹³ found that consanguinity and multisystem disease increased the likelihood of incidence of multiple genetic diagnoses in a family. Because genetics testing is a growing field, our recommendation is that diagnosis of AxD and CCD be based on clinical presentation, versus determined strictly by genetic testing. Craniofacial surgeons should have a general familiarity with the signs, symptoms, and history of a patient’s genetic disorder, prompting further evaluation for second diagnoses if the presentation of symptoms is atypical (see Table 1). Our experience emphasizes the importance of continuing to report pathogenic variants of GFAP for AxD to build on our existing compendium of variants for GFAP for quicker and more efficient diagnosis of AxD.

Table 1.

Comparing Clinical Features of CCD and AXD.

Cleidocranial Dysplasia

Juvenile Alexander Disease

•      Abnormally large, wide-open fontanelles at birth, that may remain open •      Cranium is brachycephalic •      Frontal and parietal bossing •      Hypertelorism •      Midface retrusion •      Depressed nasal bridge •      Narrow, sloping shoulders that can be brought to midline due to clavicular hypoplasia or aplasia •      Delayed eruption of secondary dentition or failure to shed primary teeth •      Brachydactyly, tapering fingers, or short, broad thumbs •      Short or moderate stature •      Normal intellect

•      Later onset, from 2 to 24 years of age, with average age of 9 years •      Macrocephaly •      Progressive bulbar symptoms •      delayed speech development •      dysarthria •      hoarseness •      increasing swallowing problems with possible vomiting •      insufficient gain in weight •      spasticity •      cerebellar ataxia •      seizures •      Autonomic dysfunction •      Ocular movement abnormalities •      Bulbar symptoms •      Atypical MRI findings •      Pathology demonstrates excessive Rosenthal fiber deposition in astrocytes

Source. Lou et al, ¹ Machol et al, ¹⁴ Zhao et al, ² and van der Knaap and Valk ¹⁵ .