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Abstract
De Sanctis-Cacchione syndrome (DCS) formerly known as xerodermic idiocy is characterised by cutaneous photosensitivity, microcephaly, mental retardation, short stature, hypogonadism, spasticity, peripheral neuropathy and sensorineural deafness. Here in, we present the case of a four and half years old male child with features of severe acute malnutrition (SAM) with a typical bird like facies and sunken eyes who had history of photosensitive pruritic pigmentary skin lesions on sun exposed areas from a very early age of six months. Gross developmental delay, ataxia, microcephaly, short stature, hypogonadism and cachectic wasting were identified on examination and hypertransaminasemia and hypothyroidism were recorded from biochemical profile. Subsequent visual evoked response and brainstem evoked response audiometry revealed anterior visual pathway dysfunction and bilateral profound sensorineural hearing loss. Magnetic resonance imaging of brain yielded subdural effusion with mass effect in addition to cerebro-cerebral atrophy and demyelination. Skin biopsy further detected dysplastic changes and early signs of squamous cell carcinoma (SCC). Although few cases are reported sporadically throughout the world, to our best of knowledge till date only 11 such cases have been reported completely in Indian medical literature which makes our case report the 12th one with distinctive novel association of subdural effusion.
Keywords: De Sanctis-Cacchione, hypogonadism, squamous cell carcinoma, subdural effusion, xeroderma pigmentosum
Introduction 
De-Sanctis and Cacchione in 1932 derived the term “xerodermic idiocy” for the three male siblings of the same family suffering from a disease characterised by skin lesions of xeroderma pigmentosum (XP) associated with intellectual disability, gonadal hypoplasia, progressive neurological deterioration, deafness and dwarfism.[1],[2] XP group of disorder is a rare autosomal recessive condition with a defective nucleotide excision repair (NER) pathway for deoxyribonucleic acid (DNA) repair with an incidence of 1 in 250,000.[1],[3] From frequent associations like mental retardation, microcephaly, delayed growth, areflexia, ataxia, cerebral atrophy to some rare alliances of optic atrophy, congenital glaucoma and schizencephaly have been reported in medical literature till date.[4] In last nine decades such sporadic cases have been identified throughout the world but only 11 cases have been reported from India, none of them mentioned subdural effusion as an associative finding [Table 1]. This makes our case the primi one to report subdural effusion as a novel alliance of De-Sanctis Cacchione syndrome (DCS) worldwide and subsequently the 12th contribution to Indian medical literature.
Table 1: Summary of published Indian case reports of De-Sanctis Cacchione syndrome along with its various associations Case Report A four and half years old first-order male-child born out of second degree consanguineous marriage presented to us with persistent dry scaly pruritic hyperpigmented photosensitive skin rash on sun exposed areas involving face, neck, upper and lower limbs, since six months of age [Figure 1]a. The child presented with severe acute malnutrition (SAM), weighing 6.4 kg (weight for age <first percentile), height 80 cm (height for age and weight for height <first percentile), mid upper arm circumference 10.2 cm (Z-score ≤4 SD) with bipedal edema and severe cachectic wasting [Figure 1]b. The child was delivered at home without any perinatal asphyxia and is not properly immunised. We noted a typical bird like facies characterised by wide forehead, microcephaly (occipitofrontal circumference: 42 cm; Z score ≤3 SD), microphthalmia, protruded ear, beaked nose and dental malocclusion without any significant nail changes. There was a presence of global developmental delay involving all domains. In addition to profound psychomotor retardation the child also had concomitant cerebellar ataxia, spastic quadriplegia, hyporeflexia and hypogonadism [Figure 1]c with rachitic skeletal deformities. Routine biochemistry including renal function was unremarkable, except transaminitis (SGPT: 182 IU/L, SGOT: 199 IU/L), vitamin D deficiency (15 ng/ml) and hypothyroidism (TSH 8.9 μIU/ml and FT4 0.6 ng/dL). We managed the child for malnutrition and administered vitamin D 3000 IU/kg, calcium 500 mg and levothyroxine 4 μg/kg/day. We advised strict photoprotection by minimising sun exposure and frequent sun screen application, eye protection and niacin supplementation for the skin lesions. Visual evoked potential (VEP) revealed bilateral anterior visual pathway dysfunction and brainstem auditory evoked response (BAER) suggested suggested profound bilateral sensorineural hearing loss. Fundoscopy of both eyes revealed normal cup disc ratio with no features of retinopathy. Non enhanced magnetic resonance imaging (NEMRI) brain revealed diffuse cerebral and cerebellar atrophy with dysmyelinating changes in bilateral supratentorial periventricular region along with subdural effusion (width 18 mm) at left cerebral convexity producing midline shift of 5 mm to right [Figure 2]. There was no past history of head injury or meningitis, thus ruling out other possible causes subdural effusion. Thereafter, the child was put on acetazolamide at 60 mg/kg/day. Skin biopsy from hypopigmented scaly lesions showed features consistent with xeroderma pigmentosum with intra-epithelial high-grade squamous cell proliferation without invasion along with keratin pearl formation [Figure 3]. De Sanctis-Cacchione syndrome was diagnosed clinically but genetic screening could not be done due to limited resources. We discharged the patient in haemodynamically stable condition and planned a monthly follow-up to monitor the progression of carcinoma, neurological evaluation and nutritional rehabilitation. However, the patient has been lost to follow-up.
Figure 1: (a) Distribution and character of pruritic hyperpigmented skin lesion of XP, (b) loss of abdominal fat with loose skin folds indicating cachectic wasting, and (c) sign of immature sexual development, hypogonadism with empty scrotal sac
Figure 3: Histopathological examination of skin biopsy showing high grade intraepithelial lesion with impending basement membrane invasion with keratin pearl formation (marked by arrowheads) 100× Discussion XP is a rare genetically heterogenous disorder with autosomal recessive inheritance caused by defective nucleotide excision repair, a crucial step of damaged DNA repair which is characterised by photosensitive cutaneous lesions, first identified by Hebra and Kaposi in 1874. XP has a higher predilection for consanguinity as evidenced by higher case incidence in India, Japan, North Africa and Middle East than Europe and North America.[5] DCS is one of the rarest subgroups of XP with most severe DNA impairment as recognised by progressive neurological degeneration, short stature, hypogonadism, sensorineural deafness with typical cutaneous changes of XP.[1] The median age of onset of symptoms is six months to three years.[6] Early age of onset and signs of neurodegeneration correlates with the disease severity.[7]
Around 18% cases of XP show variable degrees of progressive neurological deterioration and earlier any kind of neurological abnormalities along with the XP were termed as DCS. In view of overlapping clinical and genetic profile with other subgroups of XP e.g., cockayne syndrome (CS), trichothiodystrophy (TTD), DCS has been redefined to include dwarfism and immature sexual development along with the older criteria.[3] However, very few cases of complete syndrome consisting all clinical manifestations have been reported unlike ours.
Earliest neurological findings in a case of DCS are documented as high frequency deafness and hyporeflexia. The neurological symptoms appear around two years of age which become apparent with onset of cognitive decline and cerebellar dysregulation at around 4–5 years of age.[1] The common neurological manifestations of DCS as reported include psychomotor retardation, ataxia, developmental delay, hypogonadism, growth retardation, spastic quadriplegia, sensorineural deafness and peripheral neuropathy. Neuroimaging has suggested presence of cortical and olivopontocerebellar atrophy, ventricular dilatations and optic atrophy are consistent with DCS.[4],[8] Even schizencephaly, agenesis of septum pellucidum and septo-optic dysplasia have been reported as a rare radiological manifestations.[9] The aberrant radiological finding in our patient was presence of subdural effusion with its mass effect which has not been documented till date.
Absence of thickened skull bones, intracranial calcifications, cataract and pigmentary retinopathy negate the possibility of CS which has the closest resemblance.
In XP, skin neoplasms in sun exposed areas are reported to occur within first decade of life with overall incidence of 50%. Tongue cancers, non-melanoma skin cancers, melanoma, conjunctival squamous cell carcinoma (SCC) and other central nervous system (CNS) cancers are reported in decreasing order of associations. The cancers are believed to be the results of cumulative mutagenic DNA damage occurring due to impaired NER pathway and oxidative injuries.[1],[7] This patient had early features of squamous cell carcinoma as evidenced by histopathological examination of skin biopsy.
Amongst the ten complementation groups (Xeroderma pigmentosum complementation group A-G (XPA-G), xeroderma pigmentosum variant (XPV), cockayne syndrome group A (CSA), cockayne syndrome group B (CSB)) XPA gene 9q31.1 followed by XPD/ERCC2 having low DNA repair mechanism are most frequently associated with DCS. CSB gene originally discovered in CS has also been peculiarly found in some cases of DCS.[3],[10] However, genetic sequencing were not performed in our patient.
Supportive therapy is the mainstay of disease management which mainly includes photoprotection by applying sunscreen, wearing long sleeve clothes, window tinting along with eye protection, avoidance of exposure to environmental carcinogens, vitamin D supplementation in case of vitamin D insufficiency along with nutritional rehabilitation.[7],[11] A study had shown that oral isotretinoin (2 mg/kg/day) significantly reduced new onset skin cancers in patients with XP when used for two years by 63%.[12] In our patient oral isotretinoin was not used because of significant transaminitis. Our patient was put on acetazolamide for subdural effusion along with levothyroxine and nutritional rehabilitation. We also provided additional niacin supplementation as few studies have reported clinical benefits with its supplementation in XP.[13] Recently, topical application of recombinant DNA repair enzymes i.e., liposomal encapsulated T4 endonuclease V and liposomal photolyase with high protection ultraviolet fibres have shown to lower carcinogenic potential in XP,[14],[15] however this modality is unavailable in our set-up.
We have advised monthly follow-up for monitoring of neurological deterioration and progression of carcinoma as long-term follow-up is necessary in such patients.[16]
Conclusion This is the first report of De-Sanctis Cacchione syndrome, a rare XP variant with concomitant subdural effusion, to the best of our knowledge. The rarity of such association has prompted this report.
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The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
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