in 1978 allgrove and colleagues described 2 unrelated pairs of siblings with achalasia and acth insensivity , three had impaired lacrimation and one also had autonomic dysfunction . this triad ( achalasia , adrenal insufficiency and alacrima ) became known as ttriple a syndrome . during the following years several reports in the literature have focused on more global autonomic disturbances associated with allgrove syndrome leading one author to recommend the name 4a syndrome ( adreno - cortical insufficiency , achalasia of cardia , alacrima and autonomic abnormalities)[24 ] . incidence is unknown and only few numbers of families and case reports exist in literature . inheritance is autosomal recessive and most patients have consanguineous parents , but autosomal dominant forms with incomplete penetrance have also been reported [ 7 , 8 ] . mutations in the aaas gene , which encodes the product aladin , on chromosome 12q13 have been implicated as a cause of this disorder . this gene belongs to wd - repeat regulatory protein family which exhibits wide functional diversity . the encoded protein , aladin , may help regulate nucleo - cytoplasmic transport of other proteins . high expression of this protein is seen in the adrenal gland , brain and gastrointestinal tract , the organs in which the main pathologic manifestations of disease occur[914 ] . some authors believed that the pathology of this condition may be due to a progressive loss of cholinergic function throughout the body [ 8 , 15 ] . age at onset of symptoms is variable but patients usually present during the first decade of life with hypoglycemia , adrenal crisis or dysphagia . this article reports two pairs of siblings in two related families with broad clinical features of the syndrome with particular attention to premature loss of permanent teeth in two siblings . case 1 : a 13 year - old girl with unremarkable birth history was referred to our endocrinology clinic for further follow up . she was diagnosed with familial gluococorticoid insufficiency at age 4 after a hypoglycemic seizure with low cortisol and elevated acth level and was discharged on oral prednisolone . review of systems was positive for crying without tears from early infancy and darkening of skin at age 4 . by age 7 there was loosening of permanent teeth when she was l0 years old , and became near totally edentulous by the age of 13 years . blood pressure was normal without orthostatic hypotension , weight 25 kg ( z score -3 sd ) , height 132 cm ( z score -4 sd ) according to nchs growth chart . pubertal stage : breast smr ( sex maturity rating ) 1 and pubic hair smr 2 according to tanner 's staging system . she had a distinct facial appearance consisting of narrow upper lip and down  turned mouth with nasal speech . there was distal wasting in the arms , lower limb , and significant weakness of the legs . her past hospital records - before treatment with prednisolone showed normal thyroid function tests and routine biochemical and hematological tests . serum cortisol was 1.5 g / dl ( normal range 5 - 20 ) before , 3 g / dl 30 minutes and 2 g / dl 4 hours after intramuscular injection of 250 g long acting acth . ( normal response : peak plasma cortisol level greater than 19 g / dl ) . case 2 : this 15-year - old girl was second sibling of case 1 who was born of consanguineous parents . she first presented with vomiting and difficulty in swallowing at age 5 and subsequently underwent esophageal dilatations for achalasia . she also was noted to have learning difficulties , poor school performance and hearing deficit . on examination additional findings were muscular wasting , weakness and alacrima . bilateral hearing loss was confirmed by hearing evaluation . routine biochemical , hematological and serum cortisol level before and after acth stimulation test were normal . neither of the two patients had significant dental caries or periodontal disease , we did not find abnormal results in clinical and laboratory investigations for their teeth loss . case 3 : a 6-year old boy born to consanguineous parents ( cousin to cases 1 and 2 ) was referred to our clinic with darkening of skin , developmental delay and photophobia . hyperpigmentation over the knuckles of the hands and feet had developed gradually over the last 12 months . the patient 's past medical history was significant for esophageal surgery and cardiomyotomy for achalasia manifested by recurrent vomiting . on physical examination long thin face with long philtrum , narrow upper lip characteristic of allgrove syndrome was observed . the weight was 16.5 kg ( z score -2.5 standard deviation ) and the height was 103 cm ( z score -3 standard deviation ) . heart rate was 90/min and blood pressure 100/60 mmhg in supine position , but he had marked postural fall in both . schirmer 's test revealed right eye 4 mm and left eye 2 mm of wetting ( alacrima was confirmed ) . serum na , k , aldosterone , renin , thyroid function tests , bun , and creatinine were normal . serum acth level was high normal ( 53 pg / ml ; reference range 9 - 52 pg / ml ) . serum cortisol was 2.6 g / dl before , 4 g / dl 30 minutes and 2 g / d 4 hours after acth stimulation respectively . plasma levels of cortisol was measured by chemiluminescence , serum aldosterone and acth by radioimmunoassay , and rennin by immunochemiluminescence assay . based on these findings , allgrove syndrome diagnosis was established . case 4 : this 10-year - old patient is older sister of case 3 and was born with unremarkable birth history . she was evaluated because of reduced tear production and positive history of allgrove syndrome in her brother . at age 2 she was noted to have prominent neuro - developmental delay ( delay in sitting , walking and speech ) . clinical findings included distinct facial appearance characteristic of allgrove syndrome , nasal voice , dysarthria , mental retardation , ataxia ( tandem gait and finger - to - nose testing was disturbed ) . slit lamp examination and ophtalmoscopy were normal , but schirmer 's test typically showed alacrima . biochemical , hormonal and hematological screening were negative except for low cortisol and blood sugar and high acth ( serum glucose 40 mg / dl , serum cortisol 3.4 g / dl , 4 g / dl , and 2.4 g / dl , immediately before , 30 minutes and 4 hours after intramuscular injection of 250 g long acting acth , respectively ) . acth level was 60 pg / ml . in the light of these findings a diagnosis of allgrove syndrome was considered . case 1 : a 13 year - old girl with unremarkable birth history was referred to our endocrinology clinic for further follow up . she was diagnosed with familial gluococorticoid insufficiency at age 4 after a hypoglycemic seizure with low cortisol and elevated acth level and was discharged on oral prednisolone . review of systems was positive for crying without tears from early infancy and darkening of skin at age 4 . by age 7 there was loosening of permanent teeth when she was l0 years old , and became near totally edentulous by the age of 13 years . blood pressure was normal without orthostatic hypotension , weight 25 kg ( z score -3 sd ) , height 132 cm ( z score -4 sd ) according to nchs growth chart . pubertal stage : breast smr ( sex maturity rating ) 1 and pubic hair smr 2 according to tanner 's staging system . she had a distinct facial appearance consisting of narrow upper lip and down  turned mouth with nasal speech . there was distal wasting in the arms , lower limb , and significant weakness of the legs . her past hospital records - before treatment with prednisolone showed normal thyroid function tests and routine biochemical and hematological tests . serum cortisol was 1.5 g / dl ( normal range 5 - 20 ) before , 3 g / dl 30 minutes and 2 g / dl 4 hours after intramuscular injection of 250 g long acting acth . ( normal response : peak plasma cortisol level greater than 19 g / dl ) . case 2 : this 15-year - old girl was second sibling of case 1 who was born of consanguineous parents . she first presented with vomiting and difficulty in swallowing at age 5 and subsequently underwent esophageal dilatations for achalasia . she also was noted to have learning difficulties , poor school performance and hearing deficit . on examination additional findings were muscular wasting , weakness and alacrima . bilateral hearing loss was confirmed by hearing evaluation . routine biochemical , hematological and serum cortisol level before and after acth stimulation test were normal . neither of the two patients had significant dental caries or periodontal disease , we did not find abnormal results in clinical and laboratory investigations for their teeth loss . case 3 : a 6-year old boy born to consanguineous parents ( cousin to cases 1 and 2 ) was referred to our clinic with darkening of skin , developmental delay and photophobia . hyperpigmentation over the knuckles of the hands and feet had developed gradually over the last 12 months . the patient 's past medical history was significant for esophageal surgery and cardiomyotomy for achalasia manifested by recurrent vomiting . on physical examination long thin face with long philtrum , narrow upper lip characteristic of allgrove syndrome was observed . the weight was 16.5 kg ( z score -2.5 standard deviation ) and the height was 103 cm ( z score -3 standard deviation ) . heart rate was 90/min and blood pressure 100/60 mmhg in supine position , but he had marked postural fall in both . schirmer 's test revealed right eye 4 mm and left eye 2 mm of wetting ( alacrima was confirmed ) . serum na , k , aldosterone , renin , thyroid function tests , bun , and creatinine were normal . serum acth level was high normal ( 53 pg / ml ; reference range 9 - 52 pg / ml ) . serum cortisol was 2.6 g / dl before , 4 g / dl 30 minutes and 2 g / d 4 hours after acth stimulation respectively . plasma levels of cortisol was measured by chemiluminescence , serum aldosterone and acth by radioimmunoassay , and rennin by immunochemiluminescence assay . based on these findings , allgrove syndrome diagnosis was established . case 4 : this 10-year - old patient is older sister of case 3 and was born with unremarkable birth history . she was evaluated because of reduced tear production and positive history of allgrove syndrome in her brother . at age 2 she was noted to have prominent neuro - developmental delay ( delay in sitting , walking and speech ) . clinical findings included distinct facial appearance characteristic of allgrove syndrome , nasal voice , dysarthria , mental retardation , ataxia ( tandem gait and finger - to - nose testing was disturbed ) . slit lamp examination and ophtalmoscopy were normal , but schirmer 's test typically showed alacrima . biochemical , hormonal and hematological screening were negative except for low cortisol and blood sugar and high acth ( serum glucose 40 mg / dl , serum cortisol 3.4 g / dl , 4 g / dl , and 2.4 g / dl , immediately before , 30 minutes and 4 hours after intramuscular injection of 250 g long acting acth , respectively ) . acth level was 60 pg / ml . in the light of these findings a diagnosis of allgrove syndrome when adrenal insufficiency is seen in conjunction with reduced lacrimation , achalasia of cardia and autonomic neuropathy , the condition is referred to as 4a syndrome . it is a form of primary adrenal insufficiency , commonly without mineralo - corticoid deficiency . affected patients have between two and four of these main criteria , but a wide spectrum of associated features have been described including progressive central , peripheral and autonomic nervous system abnormalities , amyotrophic lateral sclerosis , pyramidal syndrome , distal motor neuropathy , dystonia , chorea , micro - cephaly[6 , 1619 , 20 ] , angular cheilitis , pes cavus , short stature , hearing deficit , xerostomia , and palmo - plantar hyper - keratosis . most cases present with classic symptoms of adrenocortical insufficiency including hypoglycemic seizures or hypotensive attacks , less frequently , a child may be evaluated initially for recurrent vomiting , hyperpigmentation , or developmental delay . we believe that clinical evaluation met the criteria for the diagnosis of allgrove syndrome in our patients . impaired intelligence , similar facial appearance characteristic of allgrove syndrome and alacrima were the most consistent clinical signs of the syndrome in our patients . lack of lacrimation was frequently present from early infancy and almost invariably before age 5 years . in review of literature alacrima was the earliest and most consistent clinical sign of allgrove syndrome[6 , 22 ] . we identified a spectrum of associated neurologic features in our cases including : impaired intelligence in all cases , significant autonomic dysfunction in case 3 , muscular wasting and weakness in case 1 and , 2 , ataxia in case3 , 4 , dysarthria in case 3 and 4 . kimber described two families who exhibited signs of multisystem neurological disease including hyperreflexia , muscle wasting , dysarthria , ataxia , optic atrophy , and intellectual impairment . kurca reported epilepsy , autonomic neuropathy and damages of central and peripheral nervous system in two brothers . chvez et al described a 21-year - old man with hyper - reflexia and muscle weakness with allgrove syndrome . our cases are remarkable in that all patients show evidence of intellectual impairment which was suggested by clinical history and confirmed by neuropsychometry . cognitive problems have been reported in some pediatric patients with allgrove syndrome in literature ( kimber et al 2003 , grant et al 1993 , moore 1991 , khalifa 1988)[2 , 4 , 6 , 25 ] , but it is unclear if this is a primary feature of the allgrove syndrome or simply a reflection of recurrent hypo - glycemia . with one exception all patients had adrenal insufficiency . glucocorticoid deficiency is hallmark of this syndrome and develops during the first two decades of life , progression from normal adrenal function to adrenal insufficiency has been described in a number of individuals[6 , 11 , 15 ] . it remains to be seen if case 2 will go on to develop adrenal insufficiency . lack of adrenal insufficiency or achalasia does not negate this diagnosis[6 , 8 , 15 ] .. two of our cases differed from other cases with premature loss of permanent teeth . we did not find possible causes of premature loss ( trauma , osteomyelitis , peri - odontal infection , xerostomia , dental caries were ruled out ) . the literature was reviewed for loss of teeth associated with this condition but it has not been described by previous investigators . chu has reported periodontal disease , multiple caries , and dry mouth in a 16-year - old hispanic boy . case 3 and 4 are currently on treatment with hydrocortisone and topical ocular lubrication with periodically follow up visits . case 1 who was the first diagnosed patient died at age 14 after a heavy stress condition ( status epilepticus ) although she received stress doses of hydrocortisone ) . by case 2 we suspect that in addition to known previous manifestations , 4-a syndrome can particularly present with loss of permanent teeth without dental caries . this could be the first report of an unusual presentation of allgrove syndrome in literature .
backgroundallgrove syndrome is a rare autosomal recessive condition characterized by adrenal insufficiency , achalasia , alacrima and occasionally autonomic disturbances . 
 mutations in the aaas gene , on chromosome 12q13 have been implicated as a cause of this disorder.case(s ) presentationwe present various manifestations of this syndrome in two related families each with two affected siblings in which several members had symptoms including reduced tear production , mild developmental delay , achalasia , neurological disturbances and also premature loss of permanent teeth in two of them.conclusionthe importance of this report is dental involvement ( loss of permanent teeth ) in allgrove syndrome that has not been reported in literature .