Pontine Tegmental Cap Dysplasia is a novel syndrome that can be easily diagnosed upon recognition of its peculiar clinical and neuroradiological features. An early diagnosis is critical to plan a complete diagnostic workup and clinical follow-up, that should include neurological, audiological and ophthalmological assessment, a skeletal X-ray, and the search for possibly associated gastrointestinal, genitourinary and cardiac defects.
The prognosis of PTCD-related phenotype appears to be highly variable. Four patients died in the first two years of life due to early complications such as recurrent aspiration pneumonias. However, it must be said that chewing and swallowing problems tend to significantly improve with age, and life expectancy considerably increases once patients have survived infancy. Indeed, of 18 patients for whom clinical details are available, five were in the second decade of life, and none of them presented any life-threatening active complication [2-3, present study].
The neuropsychological outcome of PTCD patients is also variable, ranging from severe mental retardation up to normal cognition (IQ = 94) in a 7 year old child [1
]. Our report is the first to present a detailed cognitive and behavioural assessment of PTCD patients who have reached adolescent age. Cognitive impairment in our three patients ranged from mild-moderate mental retardation to borderline IQ, with delay in adaptive functioning, visual-spatial and language deficits. Two of three patients also showed behavioural problems including mild emotional fragility, attention deficit, poor tolerance to frustration and unstable mood, although their overall socialization abilities were well preserved. These findings are in line with previous studies on children and adults with acquired cerebellar lesions or congenital cerebellar malformations, providing substantial evidence pointing to the involvement of the cerebellum in processing higher-order non-motor functions. Indeed, both acquired and congenital cerebellar lesions lead to the development of a complex behavioural pattern termed "Cerebellar Cognitive Affective Syndrome (CCAS)", characterized by cognitive disabilities with disorders of attentional functions, visual-spatial abilities, language and affectivity [11
Language impairment is a constant feature in PTCD, ranging from complete absence of language with or without sign language to a more understandable speech with severe to moderate deficit in both the expressive and receptive areas. This is mainly related to the bilateral profound hearing impairment or sensorineural deafness due to the absence or marked hypoplasia of the VIII cranial nerve. In these cases, the rehabilitative effect of hearing aids is usually weak, and it is expected that cochlear implantation also may not be effective. However, right cochlear implantation in two of our patients resulted in a significant improvement of the intelligibility of speech, increasing their self-confidence and social integration [8
The pathogenesis of PTCD is still unknown, although it has been postulated that this complex cerebellar and brainstem malformation may derive from a defect in axonal guidance and/or migration [1
]. PTCD must be distinguished from a far more common group of disorders also characterized by a peculiar mid-hindbrain malformation and presenting at birth with hypotonia and abnormal eye movements, Joubert syndrome and related disorders (JSRD) [15
]. The neuroradiological signature of JSRD is represented by the "molar tooth sign" (MTS) which stems from the association of cerebellar vermis hypo-dysplasia, deepened interpeduncular fossa, and thickened, elongated and horizontalized superior cerebellar peduncles. The absence of decussation of the superior cerebellar peduncles seems to be a shared feature in both conditions, and an "MTS-like" appearance of the midbrain has been described in some PTCD patients [1
]. However, in these cases the superior cerebellar peduncles appear laterally displaced but less elongated and horizontalized than in the classical MTS. Moreover, the typical "pontine tegmental cap" is never seen in JSRD. Clinical features are also different, insofar the multiple cranial neuropathies and the vertebral and rib anomalies that are typical of PTCD are never seen in JSRD, which pattern of multiorgan involvement includes retinopathy, progressive nephronophthisis (NPH), congenital hepatic fibrosis and polydactyly.
A correct differential diagnosis is of paramount important not only for clinical follow-up and prognosis of patients, but also to appropriately counsel the families for inheritance. In fact, JSRD are autosomal recessive disorders with a recurrence risk of one in four for each subsequent pregnancy, while the genetic basis of PTCD still remains to be determined. Both sexes are equally affected and all reported patients are sporadic, with negative family history and absence of parental consanguinity. These observations suggest that PTCD may be caused by a de novo
heterozygous autosomal genetic defect acting in a dominant manner. Recently, one patient has been described who carried a heterozygous 96 Kb deletion on chromosome 2q13 comprising the NPHP1 gene, that the authors considered causative of PTCD [3
]. The homozygous deletion of a 250 Kb genomic region encompassing the NPHP1 gene is known to cause a group of ciliopathies including isolated juvenile NPH, Senior-Löken syndrome (NPH associated with retinal dystrophy), and JSRD with NPH. Yet, it is unlikely that a heterozygous NPHP1 deletion may be pathogenically associated to PTCD. In fact, patients homozygous for the NPHP1 deletion usually inherit such genomic imbalance from asymptomatic parents, who are both heterozygous carriers. Moreover, juvenile NPH is a constant feature associated with NPHP1 deletions/mutations, that becomes clinically manifest towards the end of the first or early second decade of life with acute or chronic renal insufficiency [16
]. None of the PTCD patients described to date, including the 16 year old patient carrier of the NPHP1 deletion, presented signs of NPH or renal failure. Taken together, these observations suggest that the small chromosome 2q deletion detected in one PTCD patients may not be the genetic cause of this syndrome but just represent a coincidental finding or, possibly, a genetic modifier of the phenotype. In our study, SNP-array analysis at a resolution of 75 Kb excluded the presence of pathogenic genomic imbalances in all three patients, suggesting that point mutations in a single gene or micro-rearrangements may be causative for PTCD.
In conclusion, PTCD is a rare, but likely underestimated syndrome characterized by a peculiar cerebellar and brainstem congenital defect, and a specific constellation of clinical signs. Although the severity of the phenotypic spectrum and the extent of multiorgan involvement is variable, it is important to stress that some patients have a favorable long-term outcome, with borderline cognitive deficit or even normal cognition and partially preserved speech. Further studies on larger cohorts are needed to unravel the underlying genetic cause of this syndrome and to better understand its pathogenetic mechanisms.