Introduction
The term septo-optic dysplasia (SOD) was formed for the first time in 1956 by De Morsier [1], therefore the group of symptoms accompanying this condition is also referred as De Morsier syndrome. The septo-optic dysplasia is a rare congenital heterogeneous malformation with postulated genetic and environmental etiology with estimated incidence of 1/10000 in live births [2]. The septo-optic dysplasia is characterized by classic triad: optic nerve hypoplasia (including strabismus, nystagmus, amblyopia, blindness), midline brain malformation (absent septum pellucidum) and hypothalamic-pituitary endocrine deficiencies. Clinical diagnosis requires the pres-ence of at least two characteristics and can be confirmed by ophthalmological examination, magnetic resonance imaging (MRI), and pituitary hormone analyses. The septo-optic dysplasia is clinically heterogeneous disorder within which highly varied symptoms may occur including recurrent seizures, stereotypic movements, delayed development, visual and hearing impairment, anosmia, cardiovascu-lar anomalies and sleep disturbance [3]. The most common hormonal deficiencies affect growth hormone and gonadotropin but it can also be lower levels of the other hormones originated from hypothalamus and hypophysis such as antidiuretic hormone, corticotropin or thyrotropic hormone. Among central nervous system corpus callosum dysgenesis, schizencephaly, microphthalmos, anophthalmia, ol-factory tract hypoplasia were most often reported [4]. Diabetes insipidus (DI) is classified as central diabetes insipidus (CDI) and nephrogenic diabetes insipidus (NDI). Central diabetes insipidus is due to impaired production and/or secretion of the antidiuretic hor-mone (ADH) and this type of DI could be found in SOD. Insufficient level of ADH cause large amounts of diluted urine (polyuria), increased fluid intake (polydypsia), hypernatremia and hypokalemia. Undiagnosed DI or badly managed, is associated with a range of clinical symptoms such as severe volume depletion and electrolyte abnormalities. DI patients have an intact thirst mechanism, and there-fore they are able to maintain normal serum osmolality and volume status without clinical symptoms other than polyuria and polydipsia. Volume depletion leads to hypotension, acute kidney injury, liver injury, muscle injury and shock [5]. The signs of hypertonic encepha-lopathy are: irritability, cognitive decline, disorientation, and confusion to decreased levels of consciousness, seizure and coma [6]. The main goal for treating DI is a correction of water deficit and a reduction in the ongoing water loss from the kidney. Desmopressin has been commonly used for treating CDI. Hyponatremia is a rare complication of desmopressin therapy, which can cause severe, even fatal sequelae [7], therefore, serum electrolytes need to be monitored during the desmopressin therapy. In most cases, SOD occurs de novo and is associated with a multifactorial etiology (complex genetic susceptibility and interaction of harmful environmental factors acting in the prenatal life). Familial cases are related to SOX2, SOX3, OTX2 and HESX1 mutations [3, 8-10]. Frequently suggested causes are bleeding during the first trimester of pregnancy, alcoholism and drug abuse during pregnancy, primiparity and young maternal age [11, 12].
In this case report we describe the association of central diabetes insipidus with SOD.
Case report
The boy was born as a first child on time, in 39th week of first pregnancy by cesarean section (C-section). With 2550 grams birth weight, 49 cm body length, 30 cm head circumference and 10 points in Apgar scale he was in general good condition.
C-section was performed as a consequence of mother’s genital tract infection. Neonatal period was complicated with intrauter-ine infection and jaundice, which was treated with phototherapy. Despite periparturient period (which was complicated by maternal re-productive tract infection), the pregnancy processed correctly. In the 3rd month of pregnancy sinusitis was treated with antibiotics.
Weakened suction reflex and spitting resulted in substantial difficulties with breastfeeding, which lead to lack of gain weight. Hence the patient was hospitalized in the 1st month of life. In the screening test the otoacoustic emission did not reveal any abnormalities. Laboratory tests have shown severe anemia which required blood transfusion. After neurological examination and transfontanelle ultra-sonography central nervous system defect was suspected. In the fifth month of life MRI examination confirmed septo-optic dysplasia on the basis of anterior genu of corpus callosum and septum pellucidum agenesis, both optic nerves and optic chiasm hypoplasia, pach-ygyria and polimicrogyria of the right frontoparietal cortex. Neurological examination revealed axial laxity, psychom*otor development delay, difficulties in keeping eyes fixed as well as rotary and horizontal nystagmus. EEG waveform was abnormal with infrequently occurring generalized seizures. Ophthalmological examination showed hypoplasia of the optic nerve, severe visual impairment in the left eye, refractive error +2D in both eyes, horizontal nystagmus.
Due to the above the psychom*otor development was significantly delayed. He has reached his developmental milestones: sit-ting by the end of 2 years old, crawling – 2.5 years old, walking – 3 years old. He learnt how to mimic sounds and use simple words at the age of 3. He had been rehabilitated with Vojta and Bobath methods until age of 3. He had demonstrated aggressive behavior to-wards his parents, autoaggression and behaviors from the spectrum of autism, including: spinning in cricles, flapping, covering ears with hands.
At the age of 3 years and 5 months he underwent the endocrinological consultation due to polydipsia, polyuria and anxiety. During taking medical history the suspicion of de Morsier syndrome has been put forward. The boy drank about 6 l of fluids daily, during nights 5 diapers were used on average. Further genetic diagnosis was planned and testing for diabetes insipidus was ordered. In the physical examination boy’s weight stood at 14.5 kg and his height at 93.5 cm (3rd pc; mother’s height: 174 cm, father’s: 183 cm). Polish growth charts [13] were used to assess growth development. Urine specific gravity tests (x3); TSH level; analysis of lipids; fast-ing, 1 and 2 hours after eating glucose test were prescribed.
The tests revealed lower urine specific gravity (1,004; 1,003; 1,004 g/ml), therefore diabetes insipidus was diagnosed. The lev-els of TSH, lipids and glucose were within the normal range (Table I). Diabetes mellitus was excluded as the cause of polydipsia and polyuria. Minirin (desmopressin) 60 mg has been prescribed in initial doses 4 × 15 mg, which effectively relieved symptoms of DI. Subsequently the doses were adjusted due to blood sodium levels. On the next consultations further abnormalities were reported: long urination intervals, strabismus and poor verbal contact. At the age of 6 years and 6 months the boy still didn’t control urine passing (dia-pers needed), progressing vision impairment (foresight), trend towards constipations. The boy remains under endocrinological assess-ment.
Being 3 years and 8 months old he underwent genetic consultation. In the cytogenetic test on peripheral blood lymphocytes a normal male karyotype 46XY was demonstrated. Numerical disorders of the chromosomes and big structural abnormalities were ex-cluded. At that time the boy’s height was 92 cm (< 3rd pc), weight equaled 14.3 kg (10th pc) and head circumference was 50 cm (25th pc; Figs. 1, 2). Parents received recommendations to continue neurological, ophthalmological and endocrinological care, stimulate their child development and hearing assessment.
At the age of 3 years and 9 months boy sustained head trauma without loss of consciousness and with the presence of vomit-ing. During hospitalization due to the trauma there was no sign of skull fracture in X-ray image. However, in a short time, epileptic sei-zure occurred (hypertonia, dilated pupils, unresponsiveness to stimuli were observed). After rectal administration of diazepam symptoms subsided and have not returned. Neurological examination after the episode of seizure showed: somnolence, horizontal nystagmus, symmetrical pupils responding to light, global hypotonia, deep tendon reflexes in the norm, absence of pyramidal and meningeal symp-toms. During 15 minutes EEG recording the physiological sleep was not achieved. Numerous motor and muscle artifacts hindered the interpretation of the examination. Attempt failed due to the uncooperative child. In the short periods without artifacts seizures weren’t detected. MRI image did not show any new findings, and because of that, the diagnosis of epilepsy could not be made Low sodium levels (126 mmol/l, the next day 134 mmol/l) were detected in the hospital. Hiponatremia was observed at admission, presumably due to Minirin treatment. After stabilization of electrolyte disturbances and modification of desmopressin treatment, the symptoms let up. Dur-ing the hospitalization, spectroscopy revealed voxels localised in the posterior and anterior parts of the frontal lobes and cingulate gyrus. In voxels localised in the anterior parts of the frontal lobes high choline level (Cho/Cr) was observed (left side 1.2; right side 1.16), slightly increased also in the voxel in the posterior part of the left frontal lobe.
Currently, the boy is under a multi-disciplinary medical care. There are no signs of central diabetes insipidus. The boy requires further observation, and in the future, assessment of the functioning of the hypothalamic-pituitary axis, in particular the assessment of growth hormone deficiency and gonadotropin deficiency.
Discussion
Septo-optic dysplasia (de Morsier Syndrome) is a rare syndrome itself. The syndrome is characterized by a significant diversity of the phenotype. Thomas et al. [14] emphasized that only 30% of the patients present with the complete triad of optic nerve hypoplasia, midline central nervous system malformations and pituitary dysfunction. Concerning phenotypic variability, people suffering from SOD require multi-specialized care. The risk of hypothalamic-pituitary dysfunction in SOD is highest below 2 years of age and when both optic nerve hypoplasia and dysgenesis of septum pellucidum/corpus callosum are present [15]. Cemeroglu et al. analyze eighty children with SOD: 96% had optic nerve hypoplasia on MRI and were diagnosed due to visual issues including nystagmus (36%) or strabismus (13.8%). 51% had hypothalamic-pituitary dysfunction, when optic nerve hypoplasia was present with (36%) or without (15%) dysgen-esis of septum pellucidum and/or corpus callosum compared to dysgenesis of septum pellucidum and/or corpus callosum alone (4%) [15].
The boy presented in this case report exhibits all three features of SOD: optic nerve hypoplasia (both optic nerves and optic chiasm hypoplasia, resulting in amblyopia, hyperopia and strabismus), midline brain malformation (anterior genu of corpus callosum and septum pellucidum agenesis) and hypothalamic-pituitary endocrine deficiencies (growth deficiency, central diabetes insipidus).
Central hypothyroidism and growth hormone deficiency were most common followed by secondary/tertiary adrenal insuffi-ciency and diabetes insipidus [15]. The occurrence of vasopressin-related pituitary disorders seems to be extremely sporadic in this syn-drome. Malinowska et al. [16] presented a description of 6 pediatric patients with SOD. Six of them were diagnosed with secondary hypothyroidism, the next six with GH deficiency, three with secondary adrenal insufficiency, one with LH and FSH deficiency, and one with central diabetes insipidus [16]. The CT or MRI of the head revealed: 4 agenesis of the septum pellucidum, 2 hypoplasia of the cor-pus callosum, 1 lack of septum pellucidum and hypoplasia of the corpus callosum, 1 hypoplasia of the anterior lobe and ectoplasm of the posterior pituitary lobe, without other pathologies of the middle line of the brain [17]. In this case report, the boy presented growth defi-ciency (boy’s hight below 3rd percentile despite a very good growth potential – father’s height 183 cm, mother’s height 174 cm), howev-er we do not have knowledge, whether specific tests were conducted. Assessment of gonadotropin level disorders is currently not pos-sible, due to the fact that the boy is still before puberty. Vigilant observation and rapid response are required if the first signs of puberty do not appear at the proper time.
After the diagnosis of SOD, many clinicians pay attention to the diagnosis of growth hormone secretion and gonadotropin se-cretion, forgetting about the possibility of other disorders. The boy described in our case report was referred to the endocrine clinic, because the attention of the boy’s parents drew increased thirst and a large amount of urine output. The patient drank about 6 liters of fluid a day, simultaneously using up to 9 pampers in one night. During endocrinological consultation, the doctor paid attention to dry mucous membranes, which may indicate some degree of dehydration. The clinical picture obtained during the examination and the par-ents’ interview suggested a suspicion of diabetes insipidus.
The basic and simplest test confirming the diagnosis of DI is a general urine test, which includes urine specific gravity. The pa-tient was asked to perform three times the examination of urine specific gravity, the significant reduction of which confirmed the diagno-sis. The introduction of treatment (desmopressin) effectively eliminated the symptoms of central diabetes insipidus. DI, if well balanced by the amount of fluids consumed, may initially not reveal clinical symptoms other than polydipsia and polyuria. However, when fluid intake is insufficient, electrolyte disturbances appear.
A patient with SOD should be treated with great involvement of clinicians and the environment. The boy described in this case requires systematic monitoring of specific urine weights, daily diuresis and the amount of liquids consumed per day. Continuous moni-toring of the growth rate seems to be no less important. The boy also requires psychological, neurological and speech therapy rehabilita-tion due to the delay of development.
Conclusions
The attention should be focused on early diagnosis, treatment and education of clinicians how to recognize SOD. Abnormalities in people with SOD can vary in the severity of clinical presentation and phenotype, therefore, they require multi-specialized care. Hypopi-tuitarism ranges from isolated to multiple hormone deficits, with diabetes insipidus in a minority. Although rare, SOD is an important cause of congenital hypopituitarism and should be considered in all children with midline defects and optic nerve hyploplasia. Pituitary insufficiency may evolve over time, therefore children with SOD must be kept under endocrine follow-up. Children suffering from SOD should have development support, including motor rehabilitation, sensory and speech therapy integration.
References
1.de Morsier G. Études sur les dysraphies, crânioencéphaliques. III. Agénésie du septum palludicum avec malformation du trac-tus optique. La dysplasie septo-optique. Schweizer Archiv für Neurologie und Psychiatrie, Zurich 1956, 77: 267-292.
2.Patel L, McNally RJ, Harrison E, et al. Geographical distribution of optic nerve hypoplasia and septo-optic dysplasia in North-west England. J Pediatr 2006;148: 85-88. doi: 10.1016/j.jpeds.2005.07.031
3.Webb EA, Dattani MT. Septo-optic dysplasia. Eur J Hum Genet 2010; 18: 393-397.
4.Haddad NG, Eugster EA. Hypopituitarism and neurodevelopmental abnormalities in relation to central nervous system struc-tural defects in children with optic nerve hypoplasia. J Pediatr Endocrinol Metab 2005; 18: 853-858.
5.Lu HAJ. Diabetes Insipidus. Adv Exp Med Biol 2017; 969: 213-225. doi: 10.1007/978-94-024-1057-0_14
6.Alharfi IM, Stewart TC, Kelly SH, et al. Hypernatremia is associated with increased risk of mortality in pediatric severe trau-matic brain injury. J Neurotrauma 2013; 30: 361-366. doi: 10.1089/neu.2012.2410
7.Verrua E, Mantovani G, Ferrante E, et al. Severe water intoxication secondary to the concomitant intake of non-steroidal anti-inflammatory drugs and desmopressin: a case report and review of the literature. Hormones (Athens) 2013; 12: 135-141.
8.Dattani MT, Martinez-Barbera JP, Thomas PQ, et al. Mutations in the homeobox gene HESX1/Hesx1 associated with septo-optic dysplasia in human and mouse. Nat Genet 1998; 19: 125-133. doi: 10.1038/477
9.Kelberman D, Rizzoti K, Avilion A, et al. Mutations within Sox2/SOX2 are associated with abnormalities in the hypothalamo-pituitary-gonadal axis in mice and humans. J Clin Invest 2006; 116: 2442-2455. doi: 10.1172/JCI28658
10.Kelberman D, de Castro SC, Huang S, et al. SOX2 plays a critical role in the pituitary, forebrain and eye during human embry-onic development. J Clin Endocrinol Metab 2008; 93: 1865-1873. doi: 10.1210/jc.2007-2337
11.Garcia ML, Ty EB, Taban M, et al. Systemic and ocular findings in 100 patients with optic nerve hypoplasia. J Child Neurol 2006; 2013: 949-956. doi: 10.1177/08830738060210111701
12.Atapattu N, Ainsworth J, Willshaw H. Septo-optic dysplasia: antenatal risk factors and clinical features in a regional study. Horm Res Paediatr 2012; 2013: 81-87. doi: 10.1159/000341148
13.Palczewska I, Niedźwiecka Z. Siatki centylowe do oceny rozwoju somatycznego dzieci i młodzieży. Zakład Rozwoju Dzieci i Młodzieży Instytutu Matki i Dziecka. Warszawa 1999. [http://i.wp.pl/a/i/szkola2/pdf/siatki_centylowe.pdf (status at 12.12.18).
14.Thomas PQ, Dattani MT, Brickman JM, et al. Heterozygous HESX1 mutations associated with isolated congenital pituitary hy-poplasia and septo-optic dysplasia. Hum Mol Genet 2001; 10: 39-45.
15.Cemeroglu AP, Coulas T, Kleis L. Spectrum of clinical presentations and endocrinological findings of patients with septo-optic dysplasia: a retrospective study. J Pediatr Endocrinol Metab 2015; 28: 1057-1063. doi: 10.1515/jpem-2015-0008
16.Malinowska A, Ginalska-Malinowska M, Gajdulewicz M. Endocrine disorders in septo-optic dysplasia. Pediatric Endocrinolo-gy (Supplements) 2009; 8 (8).
