Although chromosome 1 is the largest chromosome in the human genome, only about 30 patients with interstitial microdeletions of its short arm were reported [1, 8,9,10]. Few of them [11,12,13] were described in the current microarray era and, then, the centromeric and telomeric breakpoints delimiting the exact rearranged region and the precise number of genes involved in the microdeletions were not clearly defined. Clinical features of these subjects include developmental delay, seizures, CNS malformations, macrocephaly (40% of cases), elongated or rounded face with prominent nose, micro/retrognathia, half-opened mouth, short neck, congenital heart malformations, hernia, hand/foot malformations, renal anomalies, abnormal external genitalia, joint hyperlaxity and cutis laxa [1, 5]. We identified a 20.7 Mb deletion at chromosome 1p31.3-p22.2, in an Italian female newborn with craniosynostosis (brachycephaly for premature fusion of both coronal sutures), bilateral microphthalmia and coloboma in addition to other facial dysmorphic features, cleft secondary palate, hands and foot abnormalities and severe developmental and growth delay. Unlike to the few reported cases, our patient harbors a 1p31 microdeletion spanning towards the centromere to reach the p22.2 band (less frequently reported than the involvement of the telomeric region p32) , and did not show either renal malformations or hormonal (TSH and GH) defects (Table 1).
Indeed, the interstitial deletions previously described were mainly smaller than ours and involved the chromosomal region towards the telomere including some genes which are spared in present newborn. Among these patients, the one described by Rivera-Pedroza et al. is more similar from a genetic as well as clinical point of view. This female newborn carried a 1p31.1p31.3 deletion of 18.6 Mb, and presented with a phenotype considerably overlapping with that of our proband, and including cloverleaf skull, round face, hypotelorism, severe exophthalmos with the absence of eyelids, ectopia lentis, sclerocornea, prominent nose, cleft palate, half-opened mouth, microretrognathia, low-set ears, cutis laxa, hand/foot abnormalities, congenital heart disease and developmental delay. Compared to our newborn, she additionally had bilateral renal hypoplasia, abnormal external genitalia, hernia, as well as seizures, obstructive hydrocephalus, small posterior cranial fossa and intracerebral hemorrhage.
The deleted region of the present newborn contains about ninety OMIM genes. We paid attention to about 20 of them, which are mainly those considered LoF intolerant according to their haploinsufficiency score (pLI score): IL23R, RPE65, LRRC7, SRSF11, ANKRD13C, CTH, NEGR1, TTNI3K, LHX8, ACADM, PIGK, ZZZ3, USP33, NEXN, FUBP1, ADGRL2, LPAR3, BCL10, CCN1, CLCA3P, and SH3GLB1 (Fig. 3).
Among these, IL23R (interleukin 23 receptor) may have a potential association with craniosynostosis, as already suggested by previous genetic and population analyses . Thus, although partially deleted, IL23R may be related to the craniosynostosis also in our patient. LHX8 (LIM homeobox 8) encodes a transcriptional regulator of the family LIM-homeobox, which is expressed in the first branchial arch and the basal forebrain. Its haploinsufficiency was found in patients with cleft palate in addition to microcephaly and severe learning difficulties, carrying smaller chromosome 1 deletions, and it is deleted also in our proposita. Moreover, this gene is highly expressed in connective tissue, skin and its appendages (tooth formation). Therefore, it is hard to establish a clear relation between its defect and the cutaneous abnormalities observed in 1p31 microdeletion patients, as well as the nail dysplasia observed in our newborn. RPE65 (retinoid isomerohydrolase RPE65) encodes for a protein which is a component of the vitamin A visual cycle of the retina. It is a member of the carotenoid cleavage oxygenase superfamily, and performs the essential enzymatic isomerization step in the synthesis of 11-cis retinal. Its mutations are associated with early-onset severe blinding disorders such as Leber congenital amaurosis, and it may be linked to the ocular abnormalities (microphthalmia, coloboma, retinal vessels malformations) present in our patient. LRRC7 (leucine rich repeat containing 7), GADD45A (growth arrest and DNA damage inducible alpha), and NEGR1 (neuronal growth regulator 1) are candidate genes for the developmental delay, and the psychiatric and language disorders reported in 1p31 microdeletion patients [11, 14, 15], and two of them (LRRC7 and NEGR1) are deleted in the proband (who actually presents with a severe neuromotor and language delay). Conversely, NFIA (nuclear factor IA) gene, which was associated to CNS malformations (corpus callosum and cerebellar anomalies, ventriculomegaly, hydrocephalus, tethered spinal cord, type I Chiari malformation) craniofacial abnormalities (metopic synostosis, facial dysmorphisms), developmental delay and genitourinary tract defects [16,17,18,19,20,21,22], is spared in the proposita, who actually shows only minimal morphological CNS abnormalities (isolated moderate widening of the III ventricle and kinked corpus callosum) with no genitourinary abnormalities. These findings agree with the possible involvement of such gene in renal development, but it seems unlikely its role in causing the CNS defects of present patient, although indirect mechanisms (i.e. disruption of regulatory elements) may not be excluded. LEPR (leptin receptor) and JAK1 (Janus kinase 1) haploinsufficiency were associated to abnormal pituitary development and obesity . Also these genes are not included in the deletion of our newborn, who does not show to date either hormonal (TSH and GH) abnormalities or other clinical signs of endocrine dysfunction, including excess weight.
Then, we identified and analyzed, according to literature data, the genes which may be responsible for the clinical findings of our newborn. It is hard to establish whether the other genes in the deleted centromeric region p22.3-p22.2 (i.e., LPAR3, BCL10, CCN1, SH3GLB1, HS2ST1) may also play a causative role for the phenotype of present patient, and be then considered within the critical rearrangement of 1p31 microdeletion syndrome, or more likely do not, also in light of the genomic profile (deletion of such p22.3-p22.2 genes) of the healthy mother of the proband (Fig. 3). The results of present study further confirm that microdeletions at 1p31.3 constitute a contiguous gene syndrome, whose genotype–phenotype correlations are still only partially elucidated, due to variability both in phenotype expressivity and deletion size typical of genomic disorders [24,25,26]. Further characterization of this genomic region, analysis of other patients, and functional studies will provide more insights both on the number and type of critical genes and their impact on this contiguous gene syndrome.
1p31 microdeletion syndrome must be distinguished from FGFR3-related craniosynostoses, from which it differs for associated manifestations and underlying pathogenic (genetic and molecular) mechanisms. Specifically, some suggestive clinical signs (syndactyly of hands and/or feet, ocular proptosis, ankylosis/synostosis of limb bones and cervical vertebrae), and the type of craniosynostosis (acrocephaly for early fusion of coronal and sagittal sutures, rather than brachicephaly) may help in the differential diagnosis, since they are more frequently observed in the main syndromic craniosynostoses, like Apert, Crouzon, and Pfeiffer syndromes. Neonatologists and pediatricians should take into consideration interstitial deletions of chromosome 1 in cases of developmental and growth delay associated to craniosynostosis, peculiar facial dysmorphisms, cleft palate and hand/foot abnormalities . The present report provides new data about 1p31 microdeletion syndrome, in view of a better characterization of its genomic and phenotypic profile.